of September 21 2014This information is current as

Protumor vs Antitumor Functions of IL-17

Gopal Murugaiyan and Bhaskar Saha

httpwwwjimmunolorgcontent18374169doi 104049jimmunol0901017

2009 1834169-4175 J Immunol

Referenceshttpwwwjimmunolorgcontent18374169fullref-list-1

58 of which you can access for free at cites 114 articlesThis article

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Print ISSN 0022-1767 Online ISSN 1550-6606 Immunologists Inc All rights reservedCopyright copy 2009 by The American Association of9650 Rockville Pike Bethesda MD 20814-3994The American Association of Immunologists Inc

is published twice each month byThe Journal of Immunology

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Protumor vs Antitumor Functions of IL-171

Gopal Murugaiyan and Bhaskar Saha2dagger

Inflammation appears to be a necessity for both metas-tasis and elimination of tumor cells IL-17 a proinflam-matory cytokine produced by Th17 cells contributes toboth the processes by playing a dual role in the antitu-mor immunity On one hand IL-17 promotes an anti-tumor cytotoxic T cell response leading to tumor regres-sion On the other hand by facilitating angiogenesis andegress of tumor cells from the primary focus IL-17 pro-motes tumor growth Thus the therapeutic applicationthat uses IL-17 needs to be refined by minimizing itsprotumor functions The Journal of Immunology2009 183 4169ndash4175

C hronic inflammation is associated with increased tu-mor metastasis but the mechanism of the associationremains unknown Hypoxia is proposed to be the trig-

gering factor As the tumor cells grow in mass the core of thetumor suffers from hypoxia that triggers a chain of events lead-ing to increased intratumoral vasculature These vessels func-tion as countercurrent conduits helping the tumor cells metas-tasize out of the tumor and supplying not only nutrients butalso immune cells into the tumor mass (1) Thus the inflam-mation serves two counteracting functions promoting tumorgrowth and antitumor immunity Effective antitumor immu-nity depends primarily on T cells Although IFN--secretingTh1 cells and CTLs mediate antitumor immunity the other Tcell subsets such as Foxp3-expressing regulatory T cells (Treg)3

and IL-10-secreting regulatory type 1 (Tr1) cells dampen im-munity to tumor-associated Ags and represent the main hurdlein successful antitumor immunotherapy (2ndash4) In addition theIL-17-secreting Th subset (Th17) promotes inflammation andthus may promote both tumor growth and tumor regressionSimilarly CD40 a costimulatory receptor that plays importantroles in the induction of Th1 cells and CTLs (5ndash9) is also shown toplay dual role not only in tumors (10ndash12) but also in Leishmaniainfection (13 14) Thus any factors that play dual roles such asCD40 or IL-17 in promoting both tumor growth and antitumorimmunity need to be studied in depth to minimize their protumoreffects and thereby enhance the antitumor effects

Although CD40-induced IL-12 is required for the induction ofTh1 the inflammatory Th subset lack of CD40 did not seem toimpair Th1 response as much as expected and mediated the auto-immune diseases (15 16) Mice deficient in the IL-12 subunit p35lack functional IL-12 and are still susceptible to experimental au-toimmune encephalomyelitis (EAE) In contrast p19-deficientmice are deficient in functional IL-23 and are resistant to EAE(17) Further investigation into these discrepancies led to the dis-covery of IL-17-producing CD4 T cells that were later namedTh17 cells In this review we will discuss how IL-17 also contrib-utes to the antitumor immunity rather dually although its majorfunction may be to mediate inflammation

IL-17 IL-17 receptors and Th17 cells

The cytokine IL-17 originally termed CTLA-8 was isolated asa CD4-specific transcript from a rodent cDNA library (18)Later on human IL-17 and the IL-17 receptor IL-17R werediscovered (19ndash21) With the discovery of new cytokines thatresemble it IL-17 became the founding member of a new cy-tokine family composed of six cytokines and five receptors (Ta-ble I and Refs 22ndash25) IL-17 is secreted primarily by Th17 cellsas a homodimer and can be both nonglycosylated and N-glyco-sylated In addition to Th17 cells IL-17 can also be producedby cells other than Th cells such as invariant NKT cells CD8

T cells and -T cells (26ndash28) The cytokine has pleiotropicfunctions with multiple targets IL-17R has a single trans-mem-brane domain with a long cytoplasmic tail implying the exis-tence of multiple regulatory domains such that receptor signal-ing may trigger diverse functions Discrepancies between IL-17binding constants and the concentrations needed to evoke bio-logical responses imply an additional subunit in IL-17R signal-ing (22 23 25) Although IL-17R expression is ubiquitousmost of the studies have been performed on fibroblasts osteo-blasts and epithelial cells However the structure-function re-lationship is not available for either the cytokine or its receptor

Because Th17 cells produce large quantities of IL-17A mostTh17-mediated effects are attributed to this cytokine Manyfactors are required for the induction and stabilization of Th17cells Of these TGF- and IL-6 are the most crucial cytokinesfor its differentiation IL-6 induces the production of IL-21which subsequently favors Th17 differentiation in an autocrinemanner (29 30) These cells require CD40-induced IL-23 to

Center for Neurologic Diseases Brigham and Womenrsquos Hopsital and Harvard MedicalSchool Boston MA 02120 and daggerNational Centre for Cell Science Ganeshkhind PuneIndia

Received for publication May 28 2009 Accepted for publication August 10 2009

The costs of publication of this article were defrayed in part by the payment of page chargesThis article must therefore be hereby marked advertisement in accordance with 18 USCSection 1734 solely to indicate this fact1 The work was supported by the Department of Biotechnology Government of India

2 Address correspondence and reprint requests to Dr Bhaskar Saha Scientist-F NationalCentre for Cell Science Ganeshkhind Pune 411007 India E-mail address sahabnccsresin3 Abbreviations used in this paper Treg regulatory T cell DC dendritic cell EAE ex-perimental autoimmune encephalomyelitis ROR retinoid orphan receptor VEGF vas-cular endothelial growth factor

Copyright copy 2009 by The American Association of Immunologists Inc 0022-176709$200

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maintain their Th17 phenotype in vivo The differentiation ofTh17 cells that secrete IL-17 requires the expression of the tran-scription factor ROR-t (where ROR is retinoic orphan recep-tor Ref 31) The induction of ROR-t is dependent onSTAT-3 which is preferentially activated by IL-6 IL-21 andIL-23 STAT-3-deficient T cells impair Th17 differentiationwhereas overexpression of a constitutively active form ofSTAT-3 increases IL-17 production STAT-3 affects ROR-expression and binds to the IL-17 and IL-21 promoters ThusSTAT-3 and ROR-t regulate IL-17 production in a coordi-nated manner (Fig 1)

It has been shown that Th17 cells are gradually increased in thetumor microenvironment during tumor development In addi-tion Th17 cells have been found in various tumors including my-cosis fungoides Sezary syndrome prostate and gastric cancer (Ta-ble II Refs 32ndash52) Many factors released by the tumor cells andthe tumor stroma or molecules secreted by tumor-infiltrating im-mune cells such as TGF- IL-6 PGE2 IL-21 IL-23 osteopontinIL-1 and TNF- can play major roles in the induction of Th17differentiation (53ndash56) (Fig 2) Interestingly some of these factorsare transcriptionally regulated by IL-17 thus creating positive feed-back regulation of Th17 differentiation

Regulation of Th17 differentiation in tumors

It has become clear that IL-17-roducing Th17 cells and Tregcells share a common pathway Although TGF- favors differ-entiation of naive T cells into Tregs simultaneous presence ofboth TGF- and IL-6 promotes the differentiation of Th17cells Given the tight association of TGF- and IL-6 with tu-mor incidence and progression naive T cells entering an estab-lished tumor are more likely to be exposed to conditions favor-ing Th17 differentiation TGF- favors tumor growth by

antagonizing Th1 differentiation and CTL functions such asperforin production (57) Upon stimulation with TGF- andIL-6 CD8 T cells not only lose their cytotoxic ability but arealso induced to secrete IL-17 (58) Th1 or CD8 T cell-ex-pressed IFN- inhibits angiogenesis and induces MHC class Imolecules in tumor cells thus favoring immune recognitionand the subsequent arrest of tumor growth (59) In contrastIL-17 favors angiogenesis and tumor growth therefore replac-ing IFN- with IL-17 in the tumor microenvironment mayhave severe consequences for immune recognition and surveil-lance Indeed the presence of a tumor secreting both IL-6 andTGF- causes local polarization or expansion of CD8T cellsinto an IL-17 secreting state (Tc17) Because IL-17 could po-tentially promote tumor cell survival it is possible that the IL-17-producing CD8 T cells may promote tumor growth (53)

In a developing tumor IL-17 production is further enhancedby the reciprocal regulation of IL-12 and IL-23 by PGE2 themost abundant prostanoid in epithelial cell tumors (60) Al-though IL-12 production is decreased IL-23 production is in-creased in tumors (61) Administration of PGE2 resulted inhigher expression of IL-23 and Th17 cells in the inflamed tis-sue PGE2 inhibits the induction of IL-12 and IL-27 whichinduce IFN- but inhibit IL-17 production from T cells (62)PGE2 inducing and working with IL-23 favors the expansionof human Th17 cells and enhances IL-23-induced IL-17 pro-duction by memory T cells (56) Belonging to the IL-12 familyIL-23 performs protumor functions In contrast to the antitu-mor role of IL-12 IL-23 up-regulates inflammatory processesincluding matrix metalloproteinase expression and angiogene-sis and reduces infiltration and function of CTLs (63) thuscontributing to tumor growth Indeed the IL-23p19-deficientmice are completely resistant to carcinogen-induced tumors(63) The absence of tumor formation in these mice correlatedwith the absence of various markers that are indicative oftumor-associated inflammation confirming the role of IL-23and IL-17 in tumor-promoting inflammation In fact IL-23

FIGURE 1 Differentiation and stabilization of Th17 cells Naive CD4 Tcells activated in the presence of TGF- and IL-6 initiate the Th17 differenti-ation characterized by expression of the cytokines IL-17 and IL-21 and the tran-scription factor RORt IL-21 produced by Th17 cells further amplifies Th17generation in an autocrine manner In addition IL-21 induces the IL-23 re-ceptor expression on Th17 cells to make them responsive to IL-23 stimulationDC-produced IL-23 stabilizes the Th17 phenotype and helps Th17 cells ac-quire effector functions ROR-t induction is dependent on STAT-3 which ispreferentially activated by IL-6 IL-21 and IL-23

Table I IL-17 and IL-17 receptor superfamily ligands receptors and functions

Cytokine Chromosomes Cellular Sources Receptors Major Functions

IL-17A (CTLA8) 6p12 Memory T cells IL-17RA IL-17RC Neutrophil recruitment cytokine induction inflammationIL-17B 5q32-34 Multiple tissues IL-17RB InflammationIL-17C 16g24 Unknown Unknown Modulation of Th1 cytokine productionIL-17D 13q1211 Multiple tissues Unknown Cytokine secretionIL-17E (IL-25) 14q112 Th2 IL-17RB Modulation of Th2 cytokinesIL-17F (ML-1) 6p12 CD4 T monocytes IL-17RA IL-17RC Angiogenesis

Table II List of identified tumor type with IL-17 or Th17 infiltrating cells

Cancer Type Refs

Prostate cancer 33 42ndash44Breast cancer 36 45Myeloma 39Melanoma 46Ovarian cancer 35 38 47Renal cell carcinoma 37Colon cancer 40 49 50Acute myeloid leukemia 41Gastric cancer 34Lymphoma 32 48Pancreatic cancer 51Lung cancer 52

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promotes the production of IL-17 by activated T cells (64)IL-23 is not required for triggering Th17 differentiation but iscrucial for the function survival and propagation of this T cellpopulation in the inflamed environment In contrast to the pro-tumor functions of IL-23 several reports have described the an-titumor effects of IL-23 IL-23-overexpressing tumors show re-duced growth and metastasis (65ndash69) The antitumor effects ofIL-23 in these studies were found to be mediated through theenhancement of CD8 T cell response In addition intratu-moral injection of IL-23-overexpressing dendritic cells (DCs)resulted in a similar phenotype (70) Artificial overexpression ofIL-23 induced potent antitumor immunity through variousmechanisms For example IL-23 can mediate myeloid infiltra-tion consisting of DCs macrophages and granulocytes whichcontribute to the inhibition of tumor growth and boost an im-mune reaction to these immune-sensitive tumors In additionIL-23 overexpression is likely to increase systemic IL-23 levelsleading to the growth and survival of CD8 memory T cells

IL-23 can be induced in Propionibacterium acnes-condi-tioned dendritic cells upon re-stimulation with CD154 (71) Ina model of the P acnes infection CD40-deficient animals hadimpaired IL-17 but not IFN- response The CD40 stimula-tion was instrumental in inducing IL-23 and IL-6 of which thelatter alone proved essential for Th17 differentiation delineat-ing sequential requirements for DC expression of CD40 and

production of IL-6 during Th17 polarization and revealing dis-tinct costimulatory requirements for Th1 vs Th17 generation(72) It has been shown in an EAE model that strong antigenicstimulation of T cells up-regulated CD154 expression whichin concert with certain microbial stimuli (ie cytosine phos-phate guanine curdlan and zymosan) synergistically increasedDC IL-6 production and Th17 polarization CD40 deficiencyreduced the cytokine release impaired Th17 development andsubstantially reduced EAE Thus CD40-CD40L cross-talk isimportant for Th17 development by translating strong TCRand microbial stimuli into IL-6 production (73) Consideringthe above observations in different models of infection and au-toimmunity it is possible that in a growing tumor MHC classII and CD40 expression may be low (74) due to the prevalenceof IL-4 and IL-10 IL-10 inhibits CD40 signaling as well Ex-pression of both IL-23 and IL-6 together may be reduced tolower Th17 differentiation in tumors but the same process pro-vide an intratumoral TGF--rich milieu that skews the TregTh17 reciprocity toward Treg dominance

Reciprocity between Treg and Th17 and the functional plasticity of theCD4 T cells

Although a predominant TGF- production in tumors causesTreg differentiation the addition of IL-6 shifts the Th differ-entiation to Th17 cells identifying IL-6 as a crucial factor indetermining the TregTh17 reciprocity Recent observationssuggest that IL-2 which promotes Treg expansion inhibits thegeneration of Th17 cells (75) Conversely mice lacking IL-2 orSTAT-5 which is required for IL-2R signaling had fewer Tregsbut more Th17 cells Retinoic acid metabolite secreted by DCsin tumors can reduce Th17 but not Th1 cell differentiationthrough the inhibition of IL-6 signaling and promote Treg cellgeneration by enhancing TGF--induced Foxp3 promoter ac-tivity (76) Foxp3 can bind to ROR-t and ROR- to regulateeach otherrsquos activity counteractively (77) Conditional deletionof Foxp3 recovered ROR-t activity and Th17 differentiationEven though Foxp3 alone inhibits IL-17 expression recentstudies suggest that there exists a functional plasticity betweenthese two cell types (reviewed in Refs 78 and 79) The differ-entiated Treg cells can be converted into Th17 cells under theinfluence of strong inflammatory conditions It has been shownthat under IL-6 and TCR stimulation Tregs from both the thy-mus and the periphery that down-regulated Foxp3 are con-verted to Th17 cells (80) STAT3-deficient T cells failed torepress Foxp3 upon IL-6 stimulation consistent with the re-quirement for STAT3 suppression of Foxp3 in developingTh17 cells (81) Moreover adoptive transfer of Tregs into lym-phopenic hosts resulted in the loss of Foxp3 expression and theFoxp3-negative cells could produce strong proinflammatorycytokines including IL-17 and IFN- In addition Foxp3IL-17 CD4 T cells have been observed both in vitro after po-larization in the presence of TGF- and IL-6 and in vivo inmice (82 83) Circulating human Foxp3IL-17 T cells havein vitro suppressive activity (83) Although the origin and func-tion of these coexpressors are currently unknown it is possiblethat these cells are in transition during early Treg or Th17 dif-ferentiation Accumulating evidence has demonstrated that Tregsexist in markedly higher proportions within PBMCs tumor drain-ing lymph nodes and tumor-infiltrating lymphocytes of patientswith cancer (84) Although Tregs represent the largest population

FIGURE 2 Paradoxes in the antitumor functions of Th17 Initial infiltrationof immune cells into the tumor mass results in TNF- production and activation ofthe local and newly recruited APCs inducing TGF- IL-6 IL-23 IL-12 and IL-10 TGF- alone induces regulatory T cells (iTr) which are anti-inflammatory butthe same cytokine with IL-6 induces IL-17-secreting Th17 cells which are proin-flammatory Although IL-23 stabilizes iTr and IL-10 inhibit Th17 cells On onehand PGE2 supports Th17 cells and on the other promotes Th2 differentiationwhich is possibly triggered by the NK11 T cell-secreted IL-4 Th2 cells secreteIL-4 and inhibit Th17 cells Thus PGE2 seems to play dual roles by promotingboth inflammatory Th17 and the counteracting Th2 cells Th17 cells induce in-flammation in the tumor so that the T cells and other infiltrating cells destroy thetumor Paradoxically IL-17 induces angiogenesis that helps the tumor cells metas-tasize Thus multiple factors act in concert some synergistically and some coun-teractively to regulate the Th17-mediated control of tumor growth or regressionPerhaps the conditioning of the respective cell types involved in the response andtheir temporal regulation are crucial to this control

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of CD4 T cells in progressing tumors IL-17-positive T cells ac-cumulate in parallel with Tregs within tumor tissues in mice as wellas in blood and ascites of various tumor tissues and both popula-tions reached maximal levels in advanced tumors (75) Thus theconversion of Treg cells into a IL-17-producing phenotype in thetumor microenvironment may further amplify inflammation asthey control active immune responses against tumors All of theseobservations suggest that in the tumor microenvironment the reg-ulation of Treg and Th17 proportion dictates the growth or regres-sion of tumors However Th17 cells themselves contribute to theparadox because part of their activities can both promote and re-gress tumors

The paradox of the protumor and antitumor functions of IL-17

Protumor functions of IL-17 Many functions of IL-17 in the tu-mor microenvironment contribute to tumor progression Apartfrom a minor direct effect on the proliferation and survival of tu-mor cells (34) as not all tumor cells express IL-17 receptor andrespond to IL-17 the major protumor role of IL-17 in inflamma-tion-associated cancer relies on its proangiogenic property of sur-rounding endothelial cells and fibroblasts For example IL-17-overexpressing human cervical cancer cells and nonsmall cell lungcarcinoma cells show greater ability to form tumors in immuno-compromised mice compared with control cells not overexpressingIL-17 (85 86) In addition IL-17 overexpression in fibrosarcomacells enhances their tumorigenic growth in syngenic mice owing

primarily to the proangiogenic activity of IL-17 Moreover the lev-els of Th17 cells were positively correlated with microvessel densityin tumors (87) By acting on stromal cells and fibroblasts IL-17induces a wide range of angiogenic mediators (88 89) includingvascular endothelial growth factor (VEGF) that markedly pro-mote inflammatory and tumor angiogenesis (90) IL-17 is able toup-regulate VEGF production by fibroblasts and therefore pro-mote fibroblast-induced new vessel formation in inflammationand tumors The IL-17-VEGF loop that modulates angiogenesisincludes another angiogenic factor TGF- Many cancer cells ex-press high levels of TGF- which seems to enhance cancer growthand metastasis by stimulating angiogenesis IL-17 induces VEGFwhich in turn induces TGF- and thereby VEGF-mediated an-giogenesis (91) TGF- enhances the VEGF receptivity of endo-thelial cells by increasing VEGF receptor expression (92) IL-17also induces IL-6 and PGE2 and enhances ICAM-1 expression infibroblasts All of these molecules were known to have a major rolein angiogenesis and tumor invasion (Fig 3) IL-17 appears to stim-ulate production of IL-8 (93) IL-8 signaling promotes angiogenicresponses in endothelial cells increases proliferation and survival ofendothelial and cancer cells and potentiates the migration of can-cer cells and infiltrating neutrophils at the tumor site AccordinglyIL-8 expression correlates with the angiogenesis tumorigenicityand metastasis of tumors in numerous xenograft and orthotopic invivo models (94) Moreover IL-17 was found to induce IL-1 andTNF- in macrophages and these cytokines can further synergize

FIGURE 3 Protumor vs antitumor functions of IL-17 A Protumor functions of IL-17 IL-17 signaling induces the production of both proangiogenic and protumorfactors from fibroblasts IL-17 induces VEGF which in turn induces TGF- and thereby VEGF-mediated angiogenesis TGF- enhances the VEGF receptivity byincreasing VEGF receptor expression IL-17 also induces IL-6 expression in fibroblasts Although IL-17-mediated IL-6 expression is regulated primarily by NF-B the samecytokine can further stimulate NF-B-mediated transcription of its own The increased production of IL-6 and TGF- further amplifies Th17 differentiation and creates asustained chronic inflammatory state that can favor tumor growth and metastasis B Antitumor functions of IL-17 Dendritic cells acquire process tumor-associated or tumorAgs and present epitopes to both CD4 and CD8 T cells leading to differentiation of Th17 cells and effector CTLs The differentiated Th17 cells can have multipleantitumor functions Th17 cells potentiate effector functions of both CTLs and innate effectors such as NK cells and neutrophils Th17 cells stimulate the secretion of IL-12from macrophages that leads to CTL activation Th17 cells also regulate DC maturation and effective T cell priming

4172 BRIEF REVIEWS IL-17 AND CANCER

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with IL-17 to activate neutrophil-specific chemokines thereby re-cruiting neutrophils to the site of inflammation (95)

Recently the transcription factor NF-B has been identifiedas a potential molecular bridge between inflammation and can-cer (96) However IL-17R signaling via ERK1 ERK2 JNKand p38 MAPKs results in the activation of NF-B albeitweakly (97ndash100) Although proinflammatory cytokines (egIL-6 and TNF-) chemokines (eg IL-8) PGE2 matrix met-alloproteinase and several adhesion molecules are reported torequire NF-B-mediated transcriptional activation (reviewedin Refs 24 and 101) the role of the same transcription factor inthe IL-17-mediated inflammatory responses remain to be estab-lished Although IL-17-mediated cytokine expression is regu-lated primarily by NF-B the same cytokines can further stim-ulate NF-B-mediated transcription of their own in tumor cellsand tumor-associated stromal cells thereby creating a sustainedchronic inflammatory state within the tumor microenviron-ment (Fig 3) In support of this notion enhanced cervical can-cer growth elicited by IL-17 was associated with increased ex-pression of IL-6 and macrophage recruitment to the tumor sites(86) Therefore IL-17 might also function through IL-6 to pro-mote tumor development

Chemokines can stimulate or inhibit proliferation and che-motaxis of endothelial cells of the blood vessels that serves tu-mors The balance between angiogenic and angiostatic chemo-kines in the tumor microenvironment can determine tumorsurvival When a tumor or tumor-infiltrating immune cells se-crete more of an angiogenic chemokine than an angiostatic che-mokine angiogenesis is stimulated and leads to new blood ves-sel formation and continued tumor growth In contrast anexcess of angiostatic chemokines in the tumor microenviron-ment can inhibit neovascularization and cause the subsequentarrest of tumor growth (102 103) IFN- is a potent inducer ofangiostatic cytokines (eg CXCL10) from a variety of cells in-cluding fibroblasts endothelial cells and tumor cells (104) Incontrast IL-17 has been shown to selectively enhance the pro-duction of angiogenic chemokines such as CXCL1 CXCL5CXCL6 and CXCL8 in tumor cells and epithelial cells (85105) In addition IL-17 is also known to inhibit angiostaticchemokine secretion by fibroblasts (85) Thus IL-17 may shiftthe local biologic balance between angiogenic and angiostaticchemokines toward a predominance of angiogenic chemokinesto enhance the net angiogenic activityAntitumor functions of IL-17 Although IL-17 seemed to us to be apotential tumor-promoting cytokine a sizeable number of re-ports have described tumor-inhibitory effects of IL-17 Th17-polarized cells were found to be more effective than Th1 cells ineliminating large established tumors (106) However theTh17-mediated tumor responses were highly dependent onIFN- Indeed the effects of Th17-polarized cells were com-pletely abrogated by the administration of IFN--depleting Absand not by IL-17- or IL-23-depleting Abs The Th17-polarizedcells also secreted cytokines associated with the Th17 pheno-type such as IL-17F IL-22 IL-21 and CCL20 In additionIL-17 has been shown to inhibit the growth of hematopoietictumors such as mastocytoma and plasmocytoma by enhancingCTL activity (107) Different mechanisms have been proposedfor the IL-17 enhancement of tumor-specific CTLs IL-17 hasbeen shown to induce IL-6 from variety of cells MoreoverIL-17 stimulation can induce IL-12 production from macro-phages (108) Both IL-6 and IL-12 have been associated with

the induction of tumor-specific CTL induction IL-17 pro-motes the maturation of DC progenitors as indicated by in-creased expressions of costimulatory molecules MHC class IIAgs and allostimulatory capacity (109) This may lead to fur-ther improvement in T cell priming by tumor cells producingIL-17 (Fig 3) In addition IL-17-transduced fibrosarcoma cellsinduced tumor-specific antitumor immunity by augmentingthe expression of MHC class I and class II Ags (110) Thesestudies were focused on the effects of exogenous IL-17 in estab-lished mouse tumor cell lines A recent demonstration showsthat tumor growth in subcutaneous tissue and lung tumor me-tastasis are enhanced in IL-17-deficient mice The effect is ac-companied by reduced IFN- levels in tumor-infiltrating NKcells and T cells (111) Although this study emphasizes the im-portance of endogenous IL-17 in tumor immunity in one par-ticular model it remains to be determined whether endogenousIL-17 is involved in regulating tumor immunity in other tumormodels and the involvement of other Th17-associated mole-cules such as IL-17F and IL-22 in determining tumor growthmust also be studied Although IL-17 has been shown to pro-mote tumor growth by inducing angiogenesis the same processprovides the channel through which the immune cells can in-vade and inflict an assault on the relatively inaccessible tumorcells at the core of the solid tumor mass Thus IL-17-inducedangiogenesis might also promote antitumor immunity by beinga supply channel for immune cells to reach and attack the innermass of solid tumor

ConclusionsIL-17 secreting Th cells termed Th17 cells can either stimulate orinhibit tumor growth and progression Many of the inflammatoryfunctions of IL-17 can initially benefit the host but with the al-tered tumor microenvironment IL-17 starts promoting tumorgrowth The pro-tumor vs anti-tumor effects of IL-17 are thusfunctions of the IL-17-induced inflammatory mediators and per-haps the mediators that counter-regulate IL-17 production all op-erating in tandem These factors regulate the plasticity of the T celldifferentiationmdashfrom cytotoxic CD8 T cells to IL-17-producinginflammatory CD8 T cells or from Treg to Th17 or vice ver-samdashby reprogramming the switching of gene expressions in T cells(112ndash114) Therefore to formulate a more efficient therapeuticstrategy we need to better understand the role of the factors thatregulate T cell plasticity

DisclosuresThe authors have no financial conflict of interest

References1 Murugaiyan G S Martin and B Saha 2007 CD40-induced countercurrent con-

duits for tumor escape or elimination Trends Immunol 28 467ndash4732 Zitvogel L A Tesniere and G Kroemer 2006 Cancer despite immunosurveil-

lance immunoselection and immunosubversion Nat Rev Immunol 6 715ndash7273 Wang H Y and R F Wang 2007 Regulatory T cells and cancer Curr Opin

Immunol 19 217ndash2234 Murugaiyan G S Basak and B Saha 2006 Reversal of tumor induced dendritic

cell paralysis a treatment regimen against cancer Curr Immunol Rev 2 261ndash2725 Kelsall B L E Stuber M Neurath and W Strober 1996 Interleukin-12 produc-

tion by dendritic cells the role of CD40-CD40L interactions in Th1 T-cell re-sponses Ann NY Acad Sci 795 116ndash126

6 Schoenberger S P R E Toes E I van der Voort R Offringa and C J Melief1998 T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L inter-actions Nature 393 480ndash483

7 Stumbles P A R Himbeck J A Frelinger E J Collins R A Lake andB W Robinson 2004 Cutting edge tumor-specific CTL are constitutively cross-armed in draining lymph nodes and transiently disseminate to mediate tumor regres-sion following systemic CD40 activation J Immunol 173 5923ndash5928

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8 Hsieh C S S E Macatonia C S Tripp S F Wolf A OrsquoGarra andK M Murphy 1993 Development of TH1 CD4 T cells through IL-12 producedby Listeria-induced macrophages Science 260 547ndash549

9 Curtsinger J M D C Lins and M F Mescher 2003 Signal 3 determines toler-ance versus full activation of naive CD8 T cells dissociating proliferation and devel-opment of effector function J Exp Med 197 1141ndash1151

10 Murugaiyan G R Agrawal G C Mishra D Mitra and B Saha 2007 Differen-tial CD40CD40L expression results in counteracting antitumor immune responsesJ Immunol 178 2047ndash2055

11 Murugaiyan G S Martin and B Saha 2007 Levels of CD40 expression on den-dritic cells dictate tumour growth or regression Clin Exp Immunol 149 194ndash202

12 Murugaiyan G R Agrawal G C Mishra D Mitra and B Saha 2006 Functionaldichotomy in CD40 reciprocally regulates effector T cell functions J Immunol 1776642ndash6649

13 Mathur R K A Awasthi P Wadhone B Ramanamurthy and B Saha 2004Reciprocal CD40 signals through p38MAPK and ERK-12 induce counteractingimmune responses Nat Med 10 540ndash544

14 Rub A R Dey M Jadhav R Kamat S Chakkaramakkil S MajumdarR Mukhopadhyaya and B Saha 2009 Cholesterol depletion associated with Leish-mania major infection alters macrophage CD40 signalosome composition and effec-tor function Nat Immunol 10 273ndash280

15 Perona-Wright G S J Jenkins R A OrsquoConnor D Zienkiewicz H J McSorleyR M Maizels S M Anderton and A S MacDonal 2009 A pivotal role for CD40-mediated IL-6 production by dendritic cells during IL-17 induction in vivo J Im-munol 182 2808ndash2815

16 Zhou P and R A Seder 1998 CD40 ligand is not essential for induction of type1 cytokine responses or protective immunity after primary or secondary infectionwith histoplasma capsulatum J Exp Med 187 1315ndash1324

17 Cua D J J Sherlock Y Chen C A Murphy B Joyce B Seymour L LucianW To S Kwan T Churakova et al 2003 Interleukin-23 rather than interleu-kin-12 is the critical cytokine for autoimmune inflammation of the brain Nature421 744ndash748

18 Rouvier E M F Luciani M G Mattei F Denizot and P Golstein 1993CTLA-8 cloned from an activated T cell bearing AU-rich messenger RNA instabil-ity sequences and homologous to a herpesvirus saimiri gene J Immunol 1505445ndash5456

19 Yao Z S L Painter W C Fanslow D Ulrich B M Macduff M K Spriggs andR J Armitage 1995 Human IL-17 a novel cytokine derived from T cells J Im-munol 155 5483ndash5486

20 Fossiez F O Djossou P Chomarat L Flores-Romo S Ait-Yahia C MaatJ J Pin P Garrone E Garcia S Saeland et al 1996 T cell interleukin-17 inducesstromal cells to produce proinflammatory and hematopoietic cytokines J Exp Med183 2593ndash2603

21 Shi Y S J Ullrich J Zhang K Connolly K J Grzegorzewski M C BarberW Wang K Wathen V Hodge C L Fisher et al 2000 A novel cytokine recep-tor-ligand pair identification molecular characterization and in vivo immuno-modulatory activity J Biol Chem 275 19167ndash19176

22 Yao Z W C Fanslow M F Seldin A M Rousseau S L Painter M R ComeauJ I Cohen and M K Spriggs 1995 Herpesvirus saimiri encodes a new cytokineIL-17 which binds to a novel cytokine receptor Immunity 3 811ndash821

23 Hymowitz S G E H Filvaroff J P Yin J Lee L Cai P Risser M MaruokaW Mao J Foster R F Kelley et al 2001 IL-17s adopt a cystine knot fold struc-ture and activity of a novel cytokine IL-17F and implications for receptor bindingEMBO J 20 5332ndash5341

24 Moseley T A D R Haudenschild L Rose and A H Reddi 2003 Interleukin-17family and IL-17 receptors Cytokine Growth Factor Rev 14 155ndash174

25 Gaffen S L 2004 Biology of recently discovered cytokines IL-17- a unique inflam-matory cytokine with roles in bone biology and arthritis Arthritis Res Ther 6240ndash247

26 Michel M L D Mendes-da-Cruz A C Keller M Lochner E Schneider M DyG Eberl and M C Leite-de-Moraes 2008 Critical role of ROR-t in a new thymicpathway leading to IL-17-producing invariant NKT cell differentiation Proc NatlAcad Sci USA 105 19845ndash19850

27 Ciric B M El-behi R Cabrera G X Zhang and A Rostami 2009 IL-23 drivespathogenic IL-17-producing CD8 T cells J Immunol 182 5296ndash5305

28 OrsquoBrien R L C L Roark and W K Born 2009 IL-17-producing T cells EurJ Immunol 39 662ndash666

29 Bettelli E T Korn M Oukka and V K Kuchroo 2008 Induction and effectorfunctions of TH17 cells Nature 453 1051ndash1057

30 Awasthi A G Murugaiyan and V K Kuchroo 2008 Interplay between effectorTh17 and regulatory T cells J Clin Immunol 28 660ndash670

31 Ivanov I I B S McKenzie L Zhou C E Tadokoro A Lepelley J J LafailleD J Cua and D R Littman 2006 The orphan nuclear receptor RORt directs thedifferentiation program of proinflammatory IL-17 T helper cells Cell 1261121ndash1133

32 Ciree A L Michel S Camilleri-Broet F Jean Louis M Oster B FlageulP Senet F Fossiez W H Fridman H Bachelez and E Tartour 2004 Expressionand activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezarysyndrome) Int J Cancer 112 113ndash120

33 Haudenschild D T Moseley L Rose and A Reddi 2002 Soluble and transmem-brane isoforms of novel interleukin-17 receptor-like protein by RNA splicing andexpression in prostate cancer J Biol Chem 277 4309ndash4316

34 Zhang B G Rong H Wie M Zhang J Bi L Ma X Xue G Wie X Liu andG Fang 2008 The prevalence of Th17 cells in patients with gastric cancer BiochemBiophys Res Commun 374 533ndash537

35 Kryczek I M Banerjee P Cheng L Vatan W Szeliga S Wei E HuangE Finlayson D Simeone T H Welling et al 2009 Phenotype distribution gen-

eration functional and clinical relevance of Th17 cells in the human tumor environ-ments Blood 114 1141ndash1149

36 Horlock C B Stott P J Dyson M Morishita R C Coombes P Savage andJ Stebbing 2009 The effects of trastuzumab on the CD4CD25FoxP3 andCD4IL17A T-cell axis in patients with breast cancer Br J Cancer 1001061ndash1067

37 Inozume T K Hanada Q J Wang and J C Yang 2009 IL-17 secreted by tumorreactive T cells induces IL-8 release by human renal cancer cells J Immunother 32109ndash117

38 Miyahara Y K Odunsi W Chen G Peng J Matsuzaki and R F Wang 2008Generation and regulation of human CD4 IL-17-producing T cells in ovarian can-cer Proc Natl Acad Sci USA 105 15505ndash15510

39 Dhodapkar K M S Barbuto P Matthews A Kukreja A Mazumder D VesoleS Jagannath and M V Dhodapkar 2008 Dendritic cells mediate the induction ofpolyfunctional human IL17-producing cells (Th17ndash1 cells) enriched in the bonemarrow of patients with myeloma Blood 112 2878ndash2885

40 Le Gouvello S S Bastuji-Garin N Aloulou H Mansour M T ChaumetteF Berrehar A Seikour A Charachon M Karoui K Leroy et al 2008 High prev-alence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas Gut 57772ndash779

41 Wrobel T G Mazur B Jazwiec and K Kuliczkowski 2003 Interleukin-17 inacute myeloid leukemia J Cell Mol Med 7 472ndash474

42 Derhovanessian E V Adams K Hahnel A Groeger H Pandha S Ward andG Pawelec 2009 Pretreatment frequency of circulating IL-17 CD4 T-cells butnot Tregs correlates with clinical response to whole-cell vaccination in prostate can-cer patients Int J Cancer 125 1372ndash1379

43 Sfanos K S T C Bruno C H Maris L Xu C J Thoburn A M DeMarzoA K Meeker W B Isaacs and C G Drake 2008 Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing Clin Cancer Res 143254ndash3261

44 Steiner G E M E Newman D Paikl U Stix N Memaran-Dagda C Lee andM J Marberger 2003 Expression and function of pro-inflammatory interleukinIL-17 and IL-17 receptor in normal benign hyperplastic and malignant prostateProstate 56 171ndash182

45 Zhu X L A Mulcahy R A Mohammed A H Lee H A Franks L KilpatrickA Yilmazer E C Paish I O Ellis P M Patel and A M Jackson 2008 IL-17expression by breast-cancer-associated macrophages IL-17 promotes invasiveness ofbreast cancer cell lines Breast Cancer Res 10 R95

46 von Euw E T Chodon N Attar J Jalil R C Koya B Comin-Anduix andA Ribas 2009 CTLA4 blockade increases Th17 cells in patients with metastaticmelanoma J Transl Med 7 35

47 Kato T H Furumoto T Ogura Y Onishi M Irahara S Yamano M Kamadaand T Aono 2001 Expression of IL-17 mRNA in ovarian cancer Biochem BiophysRes Commun 282 735ndash738

48 Yang Z Z A J Novak S C Ziesmer T E Witzig and S M Ansell 2009 Ma-lignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkinrsquos lymphoma Cancer Res 69 5522ndash5530

49 Gounaris E N R Blatner K Dennis F Magnusson M F Gurish T B StromP Beckhove F Gounari and K Khazaie 2009 T-regulatory cells shift from a pro-tective anti-inflammatory to a cancer-promoting proinflammatory phenotype in pol-yposis Cancer Res 69 5490ndash5497

50 Wagsater D S Lofgren A Hugander and J Dimberg 2006 Expression of inter-leukin-17 in human colorectal cancer Anticancer Res 26 4213ndash4216

51 Martin-Orozco N Y Chung S H Chang Y H Wang and C Dong 2009 Th17cells promote pancreatic inflammation but only induce diabetes efficiently in lym-phopenic hosts after conversion into Th1 cells Eur J Immunol 39 216ndash224

52 Koyama K H Kagamu S Miura T Hiura T Miyabayashi R ItohH Kuriyama H Tanaka J Tanaka H Yoshizawa et al 2008 Reciprocal CD4

T-cell balance of effector CD62LlowCD4 and CD62LhighCD25CD4 regula-tory T cells in small cell lung cancer reflects disease stage Clin Cancer Res 146770ndash6779

53 Nam J S M Terabe M J Kang H Chae N Voong Y A Yang A LaurenceA Michalowska M Mamura S Lonning et al 2008 Transforming growth factor subverts the immune system into directly promoting tumor growth through inter-leukin-17 Cancer Res 68 3915ndash3923

54 Shime H M Yabu T Akazawa K Kodama M Matsumoto T Seya andN Inoue 2008 Tumor-secreted lactic acid promotes IL-23IL-17 proinflammatorypathway J Immunol 180 7175ndash7183

55 Murugaiyan G A Mittal and H L Weiner 2008 Increased osteopontin expres-sion in dendritic cells amplifies IL-17 production by CD4 T cells in experimentalautoimmune encephalomyelitis and in multiple sclerosis J Immunol 1817480ndash7488

56 Chizzolini C R Chicheportiche M Alvarez C de Rham P Roux-LombardS Ferrari-Lacraz and J M Dayer 2008 Prostaglandin E2 synergistically with in-terleukin-23 favors human Th17 expansion Blood112 3696ndash3703

57 Massague J 2008 TGF- in cancer Cell 134 215ndash23058 Liu S J J P Tsai C R Shen Y P Sher C L Hsieh Y C Yeh A H Chou

S R Chang K N Hsiao F W Yu and H W Chen 2007 Induction of a distinctCD8 Tnc17 subset by transforming growth factor- and interleukin-6 J LeukocyteBiol 82 354ndash360

59 Blankenstein T and Z Qin 2003 The role of IFN- in tumor transplantationimmunity and inhibition of chemical carcinogenesis Curr Opin Immunol 15148ndash154

60 Greenhough A H J Smartt A E Moore H R Roberts A C WilliamsC Paraskeva and A Kaidi 2009 The COX-2PGE2 pathway key roles in the hall-marks of cancer and adaptation to the tumour microenvironment Carcinogenesis 30377ndash386

4174 BRIEF REVIEWS IL-17 AND CANCER

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61 Kortylewski M H Xin M Kujawski H Lee Y Liu T Harris C DrakeD Pardoll and H Yu 2009 Regulation of the IL-23 and IL-12 balance by Stat3signaling in the tumor microenvironment Cancer Cell 15 114ndash123

62 Sheibanie A F J H Yen T Khayrullina F Emig M Zhang R Tuma andD Ganea 2007 The proinflammatory effect of prostaglandin E2 in experimentalinflammatory bowel disease is mediated through the IL-233 IL-17 axis J Immunol178 8138ndash8147

63 Langowski J L X Zhang L Wu J D Mattson T Chen K Smith B BashamT McClanahan R A Kastelein and M Oft 2006 IL-23 promotes tumour inci-dence and growth Nature 442 461ndash465

64 Aggarwal S N Ghilardi M H Xie F J de Sauvage and A L Gurney 2003Interleukin-23 promotes a distinct CD4 T cell activation state characterized by theproduction of interleukin-17 J Biol Chem 278 1910ndash1914

65 Wang Y Q S Ugai O Shimozato L Yu K Kawamura H YamamotoT Yamaguchi H Saisho and M Tagawa 2003 Induction of systemic immunity byexpression of interleukin-23 in murine colon carcinoma cells Int J Cancer 105820ndash824

66 Shimozato O S Ugai M Chiyo H Takenobu H Nagakawa A WadaK Kawamura H Yamamoto and M Tagawa 2006 The secreted form of the p40subunit of interleukin (IL)-12 inhibits IL-23 functions and abrogates IL-23-medi-ated antitumour effects Immunology 117 22ndash28

67 Shan B L Yu O Shimozato Q Li and M Tagawa 2004 Expression of inter-leukin-21 and -23 in human esophageal tumors produced antitumor effects in nudemice Anticancer Res 24 79ndash82

68 Lo C H S C Lee P Y Wu W Y Pan J Su C W Cheng S R RofflerB L Chiang C N Lee C W Wu and M H Tao 2003 Antitumor and anti-metastatic activity of IL-23 J Immunol 171 600ndash607

69 Shan B E J S Hao Q X Li and M Tagawa 2006 Antitumor activity andimmune enhancement of murine interleukin-23 expressed in murine colon carci-noma cells Cell Mol Immunol 3 47ndash52

70 Hu J X Yuan M L Belladonna J M Ong S Wachsmann-Hogiu D L FarkasK L Black and J S Yu 2006 Induction of potent antitumor immunity by intra-tumoral injection of interleukin 23-transduced dendritic cells Cancer Res 668887ndash8896

71 Jasny E M Eisenblatter K Matz-Rensing K Tenner-Racz M TenbuschA Schrod C Stahl Hennig V Moos T Schneider P Racz et al 2008 IL-12-impaired and IL-12-secreting dendritic cells produce IL-23 upon CD154 restimu-lation J Immunol 180 6629ndash6639

72 Perona-Wright G S J Jenkins R A OrsquoConnor D Zienkiewicz H J McSorleyR M Maizels S M Anderton and A S MacDonald 2009 A pivotal role forCD40-mediated IL-6 production by dendritic cells during IL-17 induction in vivoJ Immunol 182 2808ndash2815

73 Iezzi G I Sonderegger F Ampenberger N Schmitz B J Marsland and M Kopf2009 CD40-CD40L cross-talk integrates strong antigenic signals and microbialstimuli to induce development of IL-17-producing CD4 T cells Proc Natl AcadSci USA 106 876ndash881

74 Shurin M R Z R Yurkovetsky I L Tourkova L Balki and G V Shurin 2002Inhibition of CD40 expression and CD40-mediated dendritic cell function by tu-mor-derived IL-10 Int J Cancer 101 61ndash68

75 Kryczek I S Wei L Zou S Altuwaijri W Szeliga J Kolls A Chang andW Zou 2007 Cutting edge Th17 and regulatory T cell dynamics and the regula-tion by IL-2 in the tumor microenvironment J Immunol 178 6730ndash6733

76 Mucida D Y Park G Kim O Turovskaya I Scott M Kronenberg andH Cheroutre 2007 Reciprocal TH17 and regulatory T cell differentiation mediatedby retinoic acid Science 317 256ndash260

77 Zhou L J E Lopes M M Chong I I Ivanov R Min G D Victora Y ShenJ Du Y P Rubtsov A Y Rudensky et al 2008 TGF--induced Foxp3 inhibitsTH17 cell differentiation by antagonizing RORt function Nature 453 236ndash240

78 Zhou X S Bailey-Bucktrout L T Jeker and J A Bluestone 2009 Plasticity ofCD4 FoxP3 T cells Curr Opin Immunol 21 281ndash285

79 Zhou L M M Chong and D R Littman 2009 Plasticity of CD4 T cell lineagedifferentiation Immunity 30 646ndash655

80 Xu L A Kitani I Fuss and W Strober 2007 Cutting edge regulatory T cellsinduce CD4CD25Foxp3 T cells or are self-induced to become Th17 cells in theabsence of exogenous TGF- J Immunol 178 6725ndash6729

81 Yang X O R Nurieva G J Martinez H S Kang Y Chung B P PappuB Shah S H Chang K S Schluns S S Watowich et al 2008 Molecular antag-onism and plasticity of regulatory and inflammatory T cell programs Immunity 2944ndash56

82 Voo K S Y H Wang F R Santori C Boggiano Y H Wang K Arima L BoverS Hanabuchi J Khalili E Marinova et al 2009 Identification of IL-17-producingFOXP3 regulatory T cells in humans Proc Natl Acad Sci USA 106 4793ndash4798

83 Beriou G C M Costantino C W Ashley L Yang V K KuchrooC Baecher-Allan and D A Hafler 2009 IL-17-producing human peripheral reg-ulatory T cells retain suppressive function Blood 113 4240ndash4249

84 Zou W 2006 Regulatory T cells tumour immunity and immunotherapy Nat RevImmunol 6 295ndash307

85 Numasaki M M Watanabe T Suzuki H Takahashi A NakamuraF McAllister T Hishinuma J Goto M T Lotze J K Kolls and H Sasaki 2005IL-17 enhances the net angiogenic activity and in vivo growth of human non-smallcell lung cancer in SCID mice through promoting CXCR-2-dependent angiogene-sis J Immunol 175 6177ndash6189

86 Tartour E F Fossiez I Joyeux A Galinha A Gey E Claret X Sastre-GarauJ Couturier V Mosseri V Vives et al 1999 Interleukin 17 a T-cell-derived cy-tokine promotes tumorigenicity of human cervical tumors in nude mice Cancer Res59 3698ndash3704

87 Numasaki M J Fukushi M Ono S K Narula P J Zavodny T KudoP D Robbins H Tahara and M T Lotze 2003 Interleukin-17 promotes angio-genesis and tumor growth Blood 101 2620ndash2627

88 Numasaki M M T Lotze and H Sasaki 2004 Interleukin-17 augments tumornecrosis factor--induced elaboration of proangiogenic factors from fibroblasts Im-munol Lett 93 39ndash43

89 Takahashi H M Numasaki M T Lotze and H Sasaki 2005 Interleukin-17enhances bFGF- HGF- and VEGF-induced growth of vascular endothelial cellsImmunol Lett 98 189ndash193

90 Honorati M C S Neri L Cattini and A Facchini 2006 Interleukin-17 a reg-ulator of angiogenic factor release by synovial fibroblasts Osteoarthritis Cartilage 14345ndash352

91 Jeon S H B C Chae H A Kim G Y Seo D W Seo G T Chun N S KimS W Yie W H Byeon S H Eom et al 2007 Mechanisms underlying TGF-1-induced expression of VEGF and Flk-1 in mouse macrophages and their implicationsfor angiogenesis J Leukocyte Biol 81 557ndash566

92 Huang X and C Lee 2003 Regulation of stromal proliferation growth arrestdifferentiation and apoptosis in benign prostatic hyperplasia by TGF- Front Bio-sci 8 740ndash749

93 Kehlen A K Thiele D Riemann N Rainov and J Langner 1999 Interleukin-17stimulates the expression of IB mRNA and the secretion of IL-6 and IL-8 in gli-oblastoma cell lines J Neuroimmunol 101 1ndash6

94 Waugh D J and C Wilson 2008 The interleukin-8 pathway in cancer ClinCancer Res 14 6735ndash6741

95 Aggarwal S and A L Gurney 2002 IL-17 prototype member of an emergingcytokine family J Leukocyte Biol 71 1ndash8

96 Karin M 2006 Nuclear factor-B in cancer development and progression Nature441 431ndash436

97 Shalom-Barak T J Quach and M Lotz 1998 Interleukin-17-induced gene ex-pression in articular chondrocytes is associated with activation of mitogen-activatedprotein kinases and NF-B J Biol Chem 273 27467ndash27473

98 Subramaniam S V R S Cooper and S E Adunyah 1999 Evidence for the in-volvement of JAKSTAT pathway in the signaling mechanism of interleukin-17Biochem Biophys Res Commun 262 14ndash19

99 Subramaniam S V L L Pearson and S E Adunyah 1999 Interleukin-17 inducesrapid tyrosine phosphorylation and activation of raf-1 kinase in human monocyticprogenitor cell line U937 Biochem Biophys Res Commun 259 172ndash177

100 Hunter C A Act1-ivating IL-17 inflammation 2007 Nat Immunol 8 232ndash234101 Gaffen S L 2008 An overview of IL-17 function and signaling Cytokine 43

402ndash407102 Strieter R M M D Burdick B N Gomperts J A Belperio and M P Keane

2005 CXC chemokines in angiogenesis Cytokine Growth Factor Rev 16 593ndash609103 Moore B B D A Arenberg C L Addison M P Keane P J Polverini and

R M Strieter 1998 CXC chemokines mechanism of action in regulating tumorangiogenesis Angiogenesis 2 123ndash134

104 Arenberg D A S L Kunke P J Polverini S B Morris M D BurdickM C Glass D T Taub M D Iannettoni R I Whyte and R M Strieter 1996Interferon--inducible protein 10 (IP-10) is an angiostatic factor that inhibits hu-man non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metasta-ses J Exp Med 184 981ndash992

105 Lee J W P Wang M G Kattah S Youssef L Steinman K DeFea andD S Straus 2008 Differential regulation of chemokines by IL-17 in colonic epi-thelial cells J Immunol 181 6536ndash6545

106 Muranski P A Boni P A Antony L Cassard K R Irvine A KaiserC M Paulos D C Palmer C E Touloukian K Ptak et al 2008 Tumor-specificTh17-polarized cells eradicate large established melanoma Blood 112 362ndash373

107 Benchetrit F A Ciree V Vives G Warnier A Gey C Sautes-FridmanF Fossiez N Haicheur W H Fridman and E Tartour 2002 Interleukin-17 in-hibits tumor cell growth by means of a T-cell-dependent mechanism Blood 992114ndash2121

108 Jovanovic D V J A Di Battista J Martel-Pelletier F C Jolicoeur Y HeM Zhang F Mineau and J P Pelletier 1998 IL-17 stimulates the production andexpression of proinflammatory cytokines IL- and TNF- by human macrophagesJ Immunol 160 3513ndash3521

109 Antonysamy M A W C Fanslow F Fu W Li S Qian A B Troutt andA W Thomson 1999 Evidence for a role of IL-17 in organ allograft rejectionIL-17 promotes the functional differentiation of dendritic cell progenitors J Immu-nol 162 577ndash584

110 Hirahara N Y Nio S Sasaki Y Minari M Takamura C Iguchi M DongK Yamasawa and K Tamura 2001 Inoculation of human interleukin-17 gene-transfected Meth-A fibrosarcoma cells induces T cell-dependent tumor-specific im-munity in mice Oncology 61 79ndash89

111 Kryczek I S Wei W Szeliga L Vatan and W Zou 2009 Endogenous IL-17contributes to reduced tumor growth and metastasis Blood 114 357ndash359

112 Wei G L Wei J Zhu C Zang J Hu-Li Z Yao K Cui Y Kanno T-Y RohW T Watford et al 2009 Global mapping of H3K4me3 and H3K27me3 revealsspecificity and plasticity in lineage fate determination of differentiating CD4 Tcells Immunity 30 155ndash167

113 Lee Y K H Turner C L Maynard J R Oliver D Chen C O Elson andC T Weaver 2009 Late developmental plasticity in the T helper 17 lineage Im-munity 30 92ndash107

114 Sundrud M S S M Grill D Ni K Nagata S S Alkan A Subramanian andD Unutmaz 2003 Genetic reprogramming of primary human T cells reveals func-tional plasticity in Th cell differentiation J Immunol 171 3542ndash3549

4175The Journal of Immunology

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