Role of Signal Transducer Role of Signal Transducer &Activator of &Activator of Transcription( STAT)-3 & T Transcription( STAT)-3 & T Helper (Th) 17 Cell in Helper (Th) 17 Cell in Psoriasis DevelopmentPsoriasis Development

DR M.YOUSRY ABDEL-MAWLA,MDDR M.YOUSRY ABDEL-MAWLA,MD

ZAGAZIG FACULTY OF MEDICINE,EGYPTZAGAZIG FACULTY OF MEDICINE,EGYPT

SignalSignal transducerstransducers andand activatorsactivators ofof transcriptiontranscription) ) Stat) FamilyStat) Family

StatsStats areare latentlatent inin thethe cytoplasmcytoplasm untiluntil theythey areare activatedactivated byby extracellularextracellular signalingsignaling ligandsligands, , includingincluding cytokinescytokines, , growthgrowth factorsfactors andand hormones.hormones.Binding of these extracellular ligands to the Binding of these extracellular ligands to the specific receptors leads to activation of specific receptors leads to activation of various various tyrosine kinases (TKs). tyrosine kinases (TKs). They include JAKs, receptor TKs, and non-They include JAKs, receptor TKs, and non-receptor TKs such as Src and ABL, which can receptor TKs such as Src and ABL, which can directly phosphorylate Stat proteins in the directly phosphorylate Stat proteins in the absence of ligand-induced receptor signaling absence of ligand-induced receptor signaling

Cytokines and growth factors that activate STAT proteins

Structure of STAT3 protein.Structure of STAT3 protein.

Similar to other members of the STAT family, Similar to other members of the STAT family, STAT3 is comprised of six domains: N-STAT3 is comprised of six domains: N-terminal domain, coiled-coil domain, DNA terminal domain, coiled-coil domain, DNA binding domain, linker domain, SH2 domain binding domain, linker domain, SH2 domain and Tran activation domain.and Tran activation domain.

STAT3 ActivationSTAT3 Activation

Stat3 is activated by cytokines of the IL-6 Stat3 is activated by cytokines of the IL-6 family such as IL-6, IL-11, leukemia inhibitory family such as IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M and cardiotropin I .(CNTF), oncostatin M and cardiotropin I .Stat3 is the major signal transducer Stat3 is the major signal transducer downstream of gp130-like receptorsdownstream of gp130-like receptors . .Other extracellular signaling ligands such Other extracellular signaling ligands such as IL-10 family members, epidermal growth as IL-10 family members, epidermal growth factor (EGF), platelet derived growth factor factor (EGF), platelet derived growth factor (PDGF), hepa- tocyte growth factor (HGF), (PDGF), hepa- tocyte growth factor (HGF), granulocyte colony- stimulating factor (G-granulocyte colony- stimulating factor (G-CSF) and leptin have also known to CSF) and leptin have also known to activate Stat3. activate Stat3.

Mechanism of Stat3 signalingMechanism of Stat3 signaling

Different tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such as Different tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such as EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3 EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3 through activation of intermediary kineases of the SRC and JAK families. Cytokines through activation of intermediary kineases of the SRC and JAK families. Cytokines such as IL-6 family members bind to gp130, a common receptor subunit, thereby JAK such as IL-6 family members bind to gp130, a common receptor subunit, thereby JAK families and subsequent Stat3 are activated. Non-receptor TKs such as SRC families and subsequent Stat3 are activated. Non-receptor TKs such as SRC and ABL can directly phophorylate Stat3 in the absence of ligand-dependent and ABL can directly phophorylate Stat3 in the absence of ligand-dependent receptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins form receptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins form dimers, enter the nucleus and bind DNA to activate transcription of the target genesdimers, enter the nucleus and bind DNA to activate transcription of the target genes

Regulation of the STAT3 signal Regulation of the STAT3 signal transduction pathwaytransduction pathway

Cytokine-binding induces receptor oligomerization that Cytokine-binding induces receptor oligomerization that facilitates cross-phosphorylation and activation of receptor-facilitates cross-phosphorylation and activation of receptor-associated JAK kinases. associated JAK kinases. Recruitment of STAT3 proteins to the activated receptor Recruitment of STAT3 proteins to the activated receptor complex results in their activation, dimerization and complex results in their activation, dimerization and translocation into the nucleustranslocation into the nucleusIn the nucleus they to induce the expression of cytokine-In the nucleus they to induce the expression of cytokine-responsive genes including, SOCS3 and to a lesser extent, responsive genes including, SOCS3 and to a lesser extent, SOCS1. SOCS proteins inhibit or terminate JAK/STAT signals SOCS1. SOCS proteins inhibit or terminate JAK/STAT signals by binding to tyrosine-phosphorylated JAKs and/or cytokine by binding to tyrosine-phosphorylated JAKs and/or cytokine receptors and targeting them for degradation. receptors and targeting them for degradation. The STAT3signal can also be attenuated by PIAS3, a member of The STAT3signal can also be attenuated by PIAS3, a member of the protein inhibitors of activated STATs (PIAS) family of the protein inhibitors of activated STATs (PIAS) family of proteins. PIAS3 binds selectively to activated STAT3 dimers proteins. PIAS3 binds selectively to activated STAT3 dimers and blocks their ability to activate gene transcription.and blocks their ability to activate gene transcription.

Regulation of the STAT3 signal Regulation of the STAT3 signal transduction pathwaytransduction pathway

Regulation of intracellular Stat3 Regulation of intracellular Stat3 signallingsignalling..

Effects of STAT3 Deficiency on Effects of STAT3 Deficiency on Cellular FunctionCellular Function

Stuart et al.TStuart et al.The Journal of Immunology, he Journal of Immunology, 2009, 182: 21–282009, 182: 21–28

PsoriasisPsoriasis

PsoriasisPsoriasis

Psoriasis is a chronic inflammatory skin Psoriasis is a chronic inflammatory skin disease characterized by excessive disease characterized by excessive proliferation, abnormal differentiation of proliferation, abnormal differentiation of epidermal keratino- cytes, vascular epidermal keratino- cytes, vascular proliferation, and leukocyte infiltration in the proliferation, and leukocyte infiltration in the dermis and epidermis . dermis and epidermis .

It has been considered that psoriasis It has been considered that psoriasis results from complex, aberrant relationships results from complex, aberrant relationships between the skin and immune system between the skin and immune system as as well as genetic predisposition and well as genetic predisposition and environmental factorsenvironmental factors

Psoriasis Clinical PresentationPsoriasis Clinical Presentation

Psoriasis as an immune Psoriasis as an immune disorderdisorder

Prepsoriasis StatePrepsoriasis State

Prepsoriasis StatePrepsoriasis State

Development of PsoriasisDevelopment of Psoriasis

Immunopathology of PsoriasisImmunopathology of Psoriasis

T-Cell in PsoriasisT-Cell in Psoriasis

T helper 1 versus 2 in T helper 1 versus 2 in psoriasispsoriasis

Psoriasis is an inflammatory skin disorder characterized by increased Psoriasis is an inflammatory skin disorder characterized by increased activation of CD4+ T lymphocytes, and systemic and local activation of CD4+ T lymphocytes, and systemic and local overexpression of pro-inflammatory cytokines such as interleukin 2 (IL-overexpression of pro-inflammatory cytokines such as interleukin 2 (IL-2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha, 2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha, indicating that immunopathogenesis of the disease is T helper 1 (Th1) indicating that immunopathogenesis of the disease is T helper 1 (Th1) mediated. mediated. T helper cell precursors (Thp) can be skewed towards mutually T helper cell precursors (Thp) can be skewed towards mutually exclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on exclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on the basis of the cytokine environmentthe basis of the cytokine environment..  Several studies suggest a pivotal role of bacterial superantigens in the Several studies suggest a pivotal role of bacterial superantigens in the initiation and/or exacerbation of this illness. In contrast to controls, initiation and/or exacerbation of this illness. In contrast to controls, psoriasis patients in the early course of disease were characterized by psoriasis patients in the early course of disease were characterized by significantly increased expression of the pro-inflammatory cytokine significantly increased expression of the pro-inflammatory cytokine IFN-, whilst a shift towards IL-10 secretion (Th2 response) was IFN-, whilst a shift towards IL-10 secretion (Th2 response) was observed in those presenting with increased duration of disease. observed in those presenting with increased duration of disease. These observations suggest a possible shift from a Th1 to a Th2 These observations suggest a possible shift from a Th1 to a Th2 cytokine response with superantigen-associated progression for the cytokine response with superantigen-associated progression for the duration of psoriasis, perhaps as an adaptive process by the immune duration of psoriasis, perhaps as an adaptive process by the immune system in an attempt to downregulate abnormal inflammatory Th1 system in an attempt to downregulate abnormal inflammatory Th1 immune responsesimmune responses ( (Jain etal 2009 Jain etal 2009 J Med Microbiol J Med Microbiol 5858 :180-184). :180-184).

T HELPER(TH) CELL T HELPER(TH) CELL DEVELOPMENT&DIFFERENTIATION: DEVELOPMENT&DIFFERENTIATION:

A BACKGROUNDA BACKGROUND

T-helper-cell differentiationT-helper-cell differentiation

During the initial activation of CD4+ During the initial activation of CD4+ lymphocyte, the antigen-presenting dendritic lymphocyte, the antigen-presenting dendritic cells secrete a variety of cytokines that cells secrete a variety of cytokines that instruct the naïve T cell to activate one of instruct the naïve T cell to activate one of several alternative T helper cell several alternative T helper cell developmental pathways leading to Th1, Th2, developmental pathways leading to Th1, Th2, Th17 or Treg lineage. Th17 or Treg lineage.

Each T helper phenotype produces its Each T helper phenotype produces its signature cytokines that mediate its distinct signature cytokines that mediate its distinct immunoregulatory functions.immunoregulatory functions.

T-helper-cell differentiationT-helper-cell differentiation

Activation of naïve T cells in the presence of antigen and specific cytokine signals (IFN-γ for Th1, IL-4 for Th2, and TGF-β plus IL-6 for Th17 cells) induces T cells differentiation into either Th1, Th2, or Th17 development pathways. STAT-1, STAT-4, and T-bet require for the generation of Th1 differentiation. STAT-6 and GATA-4 induces Th2 differentiation. Similarly, STAT-3, ROR-γt, and ROR-α mediates Th17differentiations pathways

J Clin Immunol (2008) 28:660–670 663

The Th1-Th2 ParadigmThe Th1-Th2 Paradigm

Naive T cell

Dendritic cell

TGF

IFN IL-4 +IL-6 -IL-6

Th1Tbet

Th2Gata 3

Th17RORT

aTregFoxP3

IL-12R

IL-12

IL-23R

IL-23

ProtectivProtective rolee role

Intracellular Intracellular pathogenspathogens

Parasitic Parasitic wormsworms

Extracellular Extracellular bacteriabacteria

Counter Counter regulationregulation

Harmful Harmful rolerole

Systemic Systemic pathologypathology

Allergy and Allergy and asthmaasthma

Autoimmunity Autoimmunity Inflammation Inflammation

CancerCancer

Adapted from Reiner et al., Cell, 2007

The Fate of Immune Responses Depends on The Fate of Immune Responses Depends on the Balance between Effector and Regulatory T the Balance between Effector and Regulatory T

cellscells

T regulatoryT effector

Features of T Helper Subsets

STAT3 & TH17 STAT3 & TH17 CELLCELL

STAT3 & Th17/Treg STAT3 & Th17/Treg developmental programsdevelopmental programs

Differentiation into Differentiation into Th17Th17 or inducible-regulatory T or inducible-regulatory T cell (cell (iTreg)iTreg) lineage has an obligatory requirement for lineage has an obligatory requirement for signals provided by TGF-b. Shortly after the signals provided by TGF-b. Shortly after the activation of naive CD4+activation of naive CD4+T cells, convergence of IL-2 and TGF-b1 signals T cells, convergence of IL-2 and TGF-b1 signals generates the common generates the common Treg/Th17Treg/Th17 precursor precursor characterized expression of Foxp3 and RORct. characterized expression of Foxp3 and RORct. Further stimulation by TGF-b1 favorsFurther stimulation by TGF-b1 favors iTreg iTreg differentiation while maturation of the differentiation while maturation of the Treg/Th17Treg/Th17 precursor in inflammatory niche with high of IL-6, precursor in inflammatory niche with high of IL-6, inhibits Foxp3 . inhibits Foxp3 . This skews development towards Th17 phenotype. This skews development towards Th17 phenotype. The Th17 master transcription factors, ROR ct and The Th17 master transcription factors, ROR ct and RORa, induce expression of IL-23 receptor through RORa, induce expression of IL-23 receptor through STAT3STAT3-dependent mechanisms,-dependent mechanisms,

STAT3 & Th17/Treg STAT3 & Th17/Treg developmental programsdevelopmental programs

T helper cell precursors being skewed towards Th1, Th2, Th17 and T T helper cell precursors being skewed towards Th1, Th2, Th17 and T

regulatory cell (Treg) phenotypes on the basis of the cytokine environmentregulatory cell (Treg) phenotypes on the basis of the cytokine environment. . 

Cytokine signaling and transcription factors in Cytokine signaling and transcription factors in

the regulation of Th17 cell differentiationthe regulation of Th17 cell differentiation..TCR stimulation activates gene expression of general transcription factors TCR stimulation activates gene expression of general transcription factors such as NFAT, AP-1, and NF-κB, and induces Th cell activation and such as NFAT, AP-1, and NF-κB, and induces Th cell activation and proliferation. proliferation. BATF is activated upon TCR stimulation and stimulates IL-17 gene BATF is activated upon TCR stimulation and stimulates IL-17 gene transcription. transcription. TGFβ stimulation induces both FoxP3 and RORγt (also RORa) activation. TGFβ stimulation induces both FoxP3 and RORγt (also RORa) activation. High concentrations of TGFb increase FoxP3 through the activation of SMAD4 High concentrations of TGFb increase FoxP3 through the activation of SMAD4 and subsequently induce TGFb production and simultaneously suppress and subsequently induce TGFb production and simultaneously suppress RORγt activity and Th17 cell differentiation. RORγt activity and Th17 cell differentiation. However, the presence of cytokine IL-6 or IL-21 activates STAT3 and induces However, the presence of cytokine IL-6 or IL-21 activates STAT3 and induces gene expression of the IL-21 and IL-23 receptor, activating positive IL-21 gene expression of the IL-21 and IL-23 receptor, activating positive IL-21 autocrine regulation for Th17 cell differentiation. autocrine regulation for Th17 cell differentiation. In addition, IL-1 induces IRF4 or epidermal FABP4, which in turn induces IL-17 In addition, IL-1 induces IRF4 or epidermal FABP4, which in turn induces IL-17 gene transcription. gene transcription. While T-bet and Ets-1 antagonize RORγt activity and thus function as While T-bet and Ets-1 antagonize RORγt activity and thus function as suppressors of Th17 cell development, suppressors of Th17 cell development, PPARγintrinsically suppresses IL-17 gene transcription by blocking the PPARγintrinsically suppresses IL-17 gene transcription by blocking the activation-induced removal of repressor complexes from the IL-17 gene activation-induced removal of repressor complexes from the IL-17 gene promoter. promoter.

Cytokine signaling and transcription factors in the regulation of Th17 cell differentiationCytokine signaling and transcription factors in the regulation of Th17 cell differentiation. TCR stimulation activates gene . TCR stimulation activates gene expression of general transcription factors such as NFAT, AP-1, and NF-κB, and induces Th cell activation and proliferation. expression of general transcription factors such as NFAT, AP-1, and NF-κB, and induces Th cell activation and proliferation. BATF is activated upon TCR stimulation and stimulates IL-17 gene transcription. TGFβ stimulation induces both FoxP3 and BATF is activated upon TCR stimulation and stimulates IL-17 gene transcription. TGFβ stimulation induces both FoxP3 and RORγt (also RORa) activation. High concentrations of TGFb increase FoxP3 through the activation of SMAD4 and subsequently RORγt (also RORa) activation. High concentrations of TGFb increase FoxP3 through the activation of SMAD4 and subsequently induce TGFb production and simultaneously suppress RORγt activity and Th17 cell differentiation. However, the presence of induce TGFb production and simultaneously suppress RORγt activity and Th17 cell differentiation. However, the presence of cytokine IL-6 or IL-21 activates STAT3 and induces gene expression of the IL-21 and IL-23 receptor, activating positive IL-21 cytokine IL-6 or IL-21 activates STAT3 and induces gene expression of the IL-21 and IL-23 receptor, activating positive IL-21 autocrine regulation for Th17 cell differentiation. In addition, IL-1 induces IRF4 or epidermal FABP4, which in turn induces IL-17 autocrine regulation for Th17 cell differentiation. In addition, IL-1 induces IRF4 or epidermal FABP4, which in turn induces IL-17 gene transcription. While T-bet and Ets-1 antagonize RORγt activity and thus function as suppressors of Th17 cell gene transcription. While T-bet and Ets-1 antagonize RORγt activity and thus function as suppressors of Th17 cell development, PPARγintrinsically suppresses IL-17 gene transcription by blocking the activation-induced removal of repressor development, PPARγintrinsically suppresses IL-17 gene transcription by blocking the activation-induced removal of repressor complexes from the IL-17 gene promoter. SOCS1 and SOCS reciprocally modulate Th17 cell differentiation. TCR, T cell complexes from the IL-17 gene promoter. SOCS1 and SOCS reciprocally modulate Th17 cell differentiation. TCR, T cell receptor; NFAT, nuclear factor of activated T cells; AP, activator protein; BATF, B cell-activating transcription factor; IL-17, receptor; NFAT, nuclear factor of activated T cells; AP, activator protein; BATF, B cell-activating transcription factor; IL-17, interleukin-17; TGFβ, transforming growth factor β; RORγt, retinoic acid-related orphan receptor γt; STAT, signal transducer interleukin-17; TGFβ, transforming growth factor β; RORγt, retinoic acid-related orphan receptor γt; STAT, signal transducer and activator of transcription; IRF-4, interferon-inducible factor-4; E-FABP, epidermal-fatty acid-binding protein; PPARγ, and activator of transcription; IRF-4, interferon-inducible factor-4; E-FABP, epidermal-fatty acid-binding protein; PPARγ, peroxisome proliferator activated receptor γ; SOCS, suppressors of cytokine signalingperoxisome proliferator activated receptor γ; SOCS, suppressors of cytokine signaling

Transcriptional regulation of TH17-cell differentiationTranscriptional regulation of TH17-cell differentiation. Na ¨ ıve CD4 T cells stimulated under the presence . Na ¨ ıve CD4 T cells stimulated under the presence of IL-6 and/or IL-21 induce activation of the signal transducer and activator of transcription of IL-6 and/or IL-21 induce activation of the signal transducer and activator of transcription 3 (STAT3).3 (STAT3). Activation of STAT3 induces the expression of retinoicacid-receptor-related orphan receptor-α (RORα) Activation of STAT3 induces the expression of retinoicacid-receptor-related orphan receptor-α (RORα) and RORγt, which establish the expression of TH-17-cell specific gene program. The role of STAT3 in and RORγt, which establish the expression of TH-17-cell specific gene program. The role of STAT3 in directly inducing IRF4 remains unclear. STAT1, downstream of IFN-γ and IL-27 signaling, or STAT5, which directly inducing IRF4 remains unclear. STAT1, downstream of IFN-γ and IL-27 signaling, or STAT5, which is downstream of IL-2 signaling, as well as ETS1, negatively regulate TH17 differentiation. Moreover, the is downstream of IL-2 signaling, as well as ETS1, negatively regulate TH17 differentiation. Moreover, the transcription factor forkhead box P3 (Foxp3), induced by transforming growth factor-β (TGF-β) signaling, transcription factor forkhead box P3 (Foxp3), induced by transforming growth factor-β (TGF-β) signaling, antagonizes the TH17-cell developmental program by directly binding to RORα or RORγt. Whether TGF-β-antagonizes the TH17-cell developmental program by directly binding to RORα or RORγt. Whether TGF-β-induced Smads or MAPKs participate in TH17 differentiation needs to be demonstrated.+induced Smads or MAPKs participate in TH17 differentiation needs to be demonstrated.+

Microbial Antigens & Th 17 ResponseMicrobial Antigens & Th 17 Response

Helper T cell (Th) commitment to Th1, Th17 and T regulatory cell (Treg) phenotypes Helper T cell (Th) commitment to Th1, Th17 and T regulatory cell (Treg) phenotypes following encounter with antigen. Production of transforming growth factor (TGF)-β by following encounter with antigen. Production of transforming growth factor (TGF)-β by naturally occurring Tregs leads to lineage commitment of precursornaturally occurring Tregs leads to lineage commitment of precursor  

ACTIVATION of T h 17 ACTIVATION of T h 17 &STAT3&STAT3

TH17 responses in mice are also TH17 responses in mice are also restrained byCD4+ regulatory T cells (Tregs)restrained byCD4+ regulatory T cells (Tregs) This suppression was lost upon Treg-specific This suppression was lost upon Treg-specific ablation of ablation of Stat3Stat3, a transcription factor critical , a transcription factor critical for for TH17 TH17 differentiation, and resulted in the differentiation, and resulted in the development of a fatal intestinal inflammation. development of a fatal intestinal inflammation. These findings suggest that Tregs adapt to These findings suggest that Tregs adapt to their environment by engaging distinct effector their environment by engaging distinct effector response–specific suppression modalities response–specific suppression modalities upon activation of STAT proteins that direct upon activation of STAT proteins that direct the corresponding class of the immune the corresponding class of the immune response(response(ChaudhryChaudhry et al,2009 et al,2009 ScienceScience 13  13 326326. no. 5955, : 986 – 991. no. 5955, : 986 – 991)) ..

STAT3 REGULATION of CYTOKINE-STAT3 REGULATION of CYTOKINE-MEDIATED GENERATION of TH 17MEDIATED GENERATION of TH 17

IL-6 functions to up-regulate IL-23R and that IL-23 synergized IL-6 functions to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi (TH17)generation. with IL-6 in promoting THi (TH17)generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor the expression of retinoic acid receptor-related orphan receptor IL-17 -T (RORt), a THi-specific transcriptional regulator. IL-17 -T (RORt), a THi-specific transcriptional regulator. STAT3 deficiency impaired ROR t expression and led to elevated STAT3 deficiency impaired ROR t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). box P3 (Foxp3). There is a pathway whereby cytokines regulate THi There is a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression (functions to regulate lineage-specific gene expression (Yang et Yang et

al.,2007 J.Biol Chem.,282,13:9358al.,2007 J.Biol Chem.,282,13:9358& Egwuagu :Cytokine 47 (2009) 149–156& Egwuagu :Cytokine 47 (2009) 149–156))..

PSORIASIS IS PSORIASIS IS Th17 Th17 DISEASE :A DISEASE :A HypothesisHypothesis

An initiating event such as trauma or skin surface An initiating event such as trauma or skin surface microbes triggers microbes triggers IL-23IL-23 production by keratinocytes production by keratinocytes and resident dendritic cells, which in turn stimulates and resident dendritic cells, which in turn stimulates proliferation of CCR4 and CCR6proliferation of CCR4 and CCR6 Th17Th17 cells found within skin. These activated cells found within skin. These activated Th17Th17 cells secrete Th17 cytokines including cells secrete Th17 cytokines including IL-22IL-22 and and IL-IL-17A17A, which cause keratinocyte growth and , which cause keratinocyte growth and activation, respectively. activation, respectively. Th17 Th17 cytokines also induce CCL20 production by cytokines also induce CCL20 production by keratinocytes, which fosters additional chemotaxis keratinocytes, which fosters additional chemotaxis of CCR6++of CCR6++Th17Th17 cells and CCR6 dendritic cells from cells and CCR6 dendritic cells from blood into skin. Cytokines released by these newly blood into skin. Cytokines released by these newly recruited cells maintain psoriatic inflammationrecruited cells maintain psoriatic inflammation

Th17 cells: effector cytokines and their function.

Th17 cells characterized by production of IL-17A, IL-17F, IL-22, and IL-21.Both IL-22 and IL-21 are not the exclusive cytokines produced byTh17 cells. IL-17A and IL-17F mediate tissue damages during organ specific autoimmunity via variety of mechanism including the activation of matrix metalloproteinases and recruitment o f neutrophils.IL-22 induces skin inflammation. IL-21 mediates amplification of T helper 17 pathway.

Proinflammatory Effects of Proinflammatory Effects of IL17IL17

Adapted from Iwakura & Ishigame, J Clin Invest 116:1218-1222 (2006)

Roles of IL-23 on T helper 17 cellsRoles of IL-23 on T helper 17 cellsin Chronic Inflammationin Chronic Inflammation

Dendritic cell

Macrophage

IL-23

IL-12

Th1

Th17

IFN

IL-1, IL-6TNF

Inflammatory response

Endothelial cellsStromal cells

Epithelial cellsFibroblasts

Macrophage

IL-17, IL-6 IL-1IL-6IL-8TNF

IL-12R

IL-23R

IL-23R

T Helper 17 Activation T Helper 17 Activation Mechanisms in PsoriasisMechanisms in Psoriasis

Cua et al., Nature 421:744, 2003Weaver et al., Immunity 24:677, 2006Mensah-Brown et al., Eur J Immunol 36:216, 2006S Hue et al. J Exp Med 11:2473, 2006

The IL23 – IL17 axis: a critical role in The IL23 – IL17 axis: a critical role in autoimmune inflammationautoimmune inflammation

IL-23 & IL-17 promote inflammatory IL-23 & IL-17 promote inflammatory bowel disease and autoimmune bowel disease and autoimmune experimental encephalomyelitisexperimental encephalomyelitis

IL-17 is overexpressed in multiple IL-17 is overexpressed in multiple sclerosis, rheumatoid arthritis and sclerosis, rheumatoid arthritis and psoriasispsoriasis

Stat3 links activated keratinocytes and Stat3 links activated keratinocytes and immunocytes required for development immunocytes required for development

of psoriasisof psoriasis Epidermal keratinocytes in psoriatic lesions are characterized Epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3. by activated Stat3. Transgenic mice with keratinocytes expressing a constitutively Transgenic mice with keratinocytes expressing a constitutively active Stat3 (active Stat3 (K5.Stat3C miceK5.Stat3C mice) develop a skin phenotype either ) develop a skin phenotype either spontaneously, or in response to wounding, that closely spontaneously, or in response to wounding, that closely resembles psoriasis.resembles psoriasis.Keratinocytes from K5.Stat3C mice show upregulation of Keratinocytes from K5.Stat3C mice show upregulation of several molecules linked to the pathogenesis of psoriasis.several molecules linked to the pathogenesis of psoriasis. In addition, the development of psoriatic lesions in K5.Stat3C In addition, the development of psoriatic lesions in K5.Stat3C mice requires cooperation between Stat3 activation in mice requires cooperation between Stat3 activation in keratinocytes and activated T cells. keratinocytes and activated T cells. Finally, abrogation of Stat3 function by a decoy oligonucleotide Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. K5.Stat3C mice. Thus, targeting Stat3Thus, targeting Stat3 may be potentially may be potentially therapeutic in the treatment of psoriasis.therapeutic in the treatment of psoriasis.

Blocking the function ofBlocking the function of STAT3STAT3 using antisense oligo-using antisense oligo-nucleotides inhibited the onset of, and reversed, established nucleotides inhibited the onset of, and reversed, established psoriatic lesionspsoriatic lesions. .

Further analysis revealed a dual requirement of both activated Further analysis revealed a dual requirement of both activated STAT3 in keratinocytes as well as in T cells, indicating that the STAT3 in keratinocytes as well as in T cells, indicating that the pathogenesis of psoriasis is rooted in a co-operative process pathogenesis of psoriasis is rooted in a co-operative process involving STAT3-regulated genes in both skin cells and the involving STAT3-regulated genes in both skin cells and the immune system .immune system .

Phosphatyrosyl peptides block STAT3-mediated DNA binding Phosphatyrosyl peptides block STAT3-mediated DNA binding activity, gene regulation and cell transformation. activity, gene regulation and cell transformation.

((VaradwajVaradwaj et al 2010 et al 2010 EgyptianEgyptian Dermatology Dermatology Online Journal 6 (1Online Journal 6 (1) ) ))

New InformationsNew Informations

Do Other Therapies Work Within This Do Other Therapies Work Within This Framework?Framework?

Anti–T-cell agents could affect Th17 Anti–T-cell agents could affect Th17 cells as they would other T cells, but cells as they would other T cells, but this needs to be clarified this needs to be clarified

Anti-TNF agents could decrease Anti-TNF agents could decrease activity of Th17 cells or work directly activity of Th17 cells or work directly on keratinocyte responseson keratinocyte responses

Studies on Stat 3 in PsoriasisStudies on Stat 3 in Psoriasis

Stat 3 in PsoriasisStat 3 in Psoriasis

New Prospectives &DirectionsNew Prospectives &Directions

Manipulation of PsorasisManipulation of Psorasis

Therapeutic Targets in Therapeutic Targets in Psoriasis As a T Helper 17 Psoriasis As a T Helper 17

Cell DiseaseCell Disease

IL-12/IL-23 Inhibitors in PsoriasisIL-12/IL-23 Inhibitors in Psoriasis

Kauffman et al., J Invest Dermatol 123: 1037, 2004Kauffman et al., J Invest Dermatol 123: 1037, 2004

Krueger et al., Krueger et al., N Engl J Med 356: 580, 2007 N Engl J Med 356: 580, 2007

Torti et al., J Am Acad Dermatol, Torti et al., J Am Acad Dermatol, 10.1016/j.jaad.2007.07.01610.1016/j.jaad.2007.07.016  

Reviewed in Torti et al., J Am Acad Dermatol, 2007 doi: 10.1016/j.jaad.2007.07.016 

IL-12/IL-23 as Therapeutic Targets IL-12/IL-23 as Therapeutic Targets in Psoriasisin Psoriasis

Role of IL-12/IL-23 in Mouse ModelsRole of IL-12/IL-23 in Mouse ModelsExperimental psoriasis is abolished by anti-p40 Ab therapyExperimental psoriasis is abolished by anti-p40 Ab therapy

Transgenic overexpression of p40 results in skin inflammationTransgenic overexpression of p40 results in skin inflammation

IL-23 injection results in skin inflammationIL-23 injection results in skin inflammation

Expression of IL-12/IL-23 in Human PsoriasisExpression of IL-12/IL-23 in Human Psoriasisp40 mRNA and protein are increased in psoriatic lesionsp40 mRNA and protein are increased in psoriatic lesions

p19 mRNA and protein are increased in psoriatic lesionsp19 mRNA and protein are increased in psoriatic lesions

IL-12 and IL-23 decrease after conventional psoriatic therapyIL-12 and IL-23 decrease after conventional psoriatic therapy

A polymorphism in p40 gene is associated with susceptibility to psoriasisA polymorphism in p40 gene is associated with susceptibility to psoriasis

Clinical Studies with anti-p40 mAbClinical Studies with anti-p40 mAb

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STAT3STAT3 protein has emerged as an important determinant of protein has emerged as an important determinant of whether the naïve T cell differentiates into regulatory (whether the naïve T cell differentiates into regulatory (Treg)Treg) or or an inflammatory (an inflammatory (Th17)Th17) T cell lineage. T cell lineage. STAT3 STAT3 also has potent anti-inflammatory effects and regulates also has potent anti-inflammatory effects and regulates critical cellular processes such as, cell growth, apoptosis and critical cellular processes such as, cell growth, apoptosis and transcription of inflammatory genes. transcription of inflammatory genes. Dysregulation of Dysregulation of STAT3STAT3 pathway has therefore been implicated pathway has therefore been implicated in the development of chronic inflammatory diseases, as well in the development of chronic inflammatory diseases, as well as, a number of malignant and neurodegenerative diseases. as, a number of malignant and neurodegenerative diseases. New insights from animal models of psoriasis as an exemplar New insights from animal models of psoriasis as an exemplar of critical roles that of critical roles that STAT3STAT3 pathways play in inflammatory pathways play in inflammatory diseases including psoriasis and on how inhibiting diseases including psoriasis and on how inhibiting STAT3STAT3 can be exploited to mitigate pathogenic autoimmunity(can be exploited to mitigate pathogenic autoimmunity(Egwuagu Egwuagu Cytokine 47 (2009) 149–156Cytokine 47 (2009) 149–156))

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Stat3 is Key intracellular signaling Stat3 is Key intracellular signaling molecule important in Th17 molecule important in Th17 development and mediates IL-22–development and mediates IL-22–induced keratinocyte hyperproliferation.induced keratinocyte hyperproliferation.

Blocking of stat3 pathway is good-to-Blocking of stat3 pathway is good-to-excellent (similar to TNF-a inhibitors): excellent (similar to TNF-a inhibitors): major signaling pathway inhibition major signaling pathway inhibition may have expected good clinical may have expected good clinical results in psoriasis .results in psoriasis .

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