Hypotheses on the role of cytokines in peptic ulcer disease

European Journal of Clinical Investigation (1998) 28, 511–519 Paper 306

Review

Hypotheses on the role of cytokines in peptic ulcer disease

F. S. Lehmann and G. A. StalderUniversity Hospital of Basle, Basle, Switzerland

Abstract Helicobacter pylori is the cause of chronic type B gastritis and occurs in almost all patientswith duodenal ulcers. Infection with H. pylori is characterized by an increased production ofseveral inflammatory cytokines. Increasing evidence suggests a central role of these cytokinesin the pathogenesis of H. pylori-associated gastritis and peptic ulcer disease. Cytokines maybe crucial in the recruitment and activation of inflammatory cells and in stimulation ofgastrin release. In addition to their proinflammatory properties, cytokines may also inhibitthe ulcer occurrence by stimulation of prostaglandins and somatostatin release and by directimpairment of acid secretion. The balance of these factors may determine the clinicaloutcome of H. pylori infection.

Keywords Cytokines, Helicobacter, interleukin, tumour necrosis factor, ulcer.Eur J Clin Invest 1998; 28 (7): 511–519

Introduction

Cytokines play a critical role in the pathogenesis of mucosalinflammation and are considered to be crucial for thedevelopment of inflammatory bowel disease [1]. In com-parison, the state of knowledge about the involvementof cytokines in the pathogenesis of Helicobacter pylori-associated gastritis and peptic ulcer disease is still at anearly stage. This article focuses on the importance ofcytokines for the development of peptic ulcers anddescribes their effects on gastric mucosal inflammation,gastrin and somatostatin release, and acid secretion.

Cytokine production in H. pylori-associatedgastritis

H. pylori is the major aetiological agent of chronic diffusesuperficial gastritis and occurs in almost all patients withduodenal ulcers [2]. The bacterium resides within orbeneath the antral mucus in close association with theepithelium [3]. The presence of H. pylori in the gastricantrum is associated with mucosal inflammatory cells [3],

such as neutrophils, lymphocytes, monocytes/macrophagesand plasma cells [2].

Infection with H. pylori is characterized by an increasedproduction of mucosal inflammatory cytokines such astumour necrosis factor (TNF)-a [4,5], interleukin (IL)-1b [5,6], IL-2 [6], IL-6 [4,7], IL-7 [8], IL-8 [6,7,9] andleukotriene (LT) B4 [10] (Fig. 1). In addition, interferon(IFN)-g secreting cells are increased in gastritis with andwithout H. pylori [11]. A correlation between the mucosallevel of IL-8 and TNF-a and the histological activity in H.pylori-associated gastritis has been reported recently [6,12].IL-8 and TNF-a mRNA/rRNA significantly decrease aftercure of the infection indicating an increased synthesis of thesecytokines in H. pylori-associated antral gastritis [13].

The cellular source of cytokines involved in H. pylori-induced gastritis has intensively been studied only for IL-8.IL-8 can be produced by a variety of cell types, includingmacrophages, T cells, fibroblasts, endothelial and epithelialcells [12]. Current evidence suggests that gastric epithelialcells may be the main producers of IL-8 in H. pyloriinfection [14–16]. Studies in human gastric epithelialcarcinoma cells indicate that the synthesis of IL-8 involvesprotein kinase C as well as tyrosine kinase activity [17]. Thecellular source of IL-1b, TNF-a, IL-6, IFN-g and IL-2 in H.pylori-associated gastritis is not known. IL-1b and TNF-amay be mainly secreted by activated macrophages [1], IFN-gand IL-2 by T lymphocytes or natural killer cells [11,18].

H. pylori-induced activation of cytokine release

H. pylori secretes a potent chemotactic factor, possibly

Q 1998 Blackwell Science Ltd

Division of Gastroenterology, University Hospital of Basle, 4031Basle, Switzerland (F. S. Lehmann, G. A. Stalder).

Correspondence to: F. Lehmann, Division of Gastroenterology,University Hospital of Basle, 4031 Basle, Switzerland.

Received 15 July 1997; accepted 15 January 1998

512 F. S. Lehmann and G. A. Stalder

urease, for mononuclear and polypmorphonuclear inflam-matory cells [19–21] and stimulates monocytes tosecrete IL-1b, IL-6, IL-8, and TNF-a [22–25]. Monocyteactivation is shown by the expression of surface IL-2receptors and increased expression of HLA-DR [22]. Maiet al. [3] have suggested that the stimulation of monocytesoccurred by lipopolysaccharide (LPS)-dependent andLPS-independent mechanisms. The LPS of many Gram-negative bacteria is a major stimulus of TNF-a secretion[26] and induces IL-6 and IL-8 [5,14]. However, theimportance of LPS for H. pylori-induced activation ofmonocytes has been questioned, and urease has recentlybeen demonstrated to stimulate specifically the synthesis ofIL-1b, IL-6, IL-8 and TNF-a by activated monocytes [22].As H. pylori does not appear to invade the gastric mucosa,the absorption of secreted soluble surface proteins such asurease could be a key factor in the H. pylori-inducedactivation of inflammatory cells [3,21].

Recruitment and activation of inflammatorycells

Recruitment of neutrophils and mononuclear cells to thesite of inflammation is an important step in the pathogen-esis of H. pylori-associated gastritis. Increased expression ofadhesion molecules on endothelial cells enables neutro-phils, monocytes and lymphocytes to adhere to bloodvessels. This effect seems to be primarily mediated by IL-1b [7], IL-8 [27], IFN-g and TNF-a [1] (Fig. 2). Thesubsequent migration of neutrophils and mononuclearcells into the inflammatory site may be further stimulatedby IL-8 [27,28], IL-1b [7,29], TGF-b, LT B4 and platelet-activating factor [1]. The chemotactic activity of IL-1b

seems to be primarily due to the induction of local IL-8production [30,31].

After migration to the inflammatory site, neutrophils,lymphocytes and monocytes/macrophages are activated bythe local action of cytokines. The subsequent release oftoxic metabolites and lysosomal enzymes may be respon-sible for the local tissue damage in peptic ulcer disease

[4,6,32]. IL-6 [33,34] and IL-8 [27,35] have been shownto activate neutrophils inducing the oxidative burst andlysozyme secretion. IL-1b stimulates neutrophils andmononuclear inflammatory cells [7], however much ofthis effect seems to be due to the induction of local IL-8production [30,31]. In addition, IL-6 and IL-1b may beinvolved in the stimulation of acute-phase protein synthesis[7,36]. TNF-a stimulates the respiratory burst anddegranulation in neutrophils [37], probably contributingto the mucosal destruction in peptic ulcers [3].

HLA class II expression

In normal gastric mucosa, epithelial HLA-DR expressionvirtually never occurs. In H. pylori-associated, chronic typeB gastritis, a variable degree of epithelial HLA-DR expres-sion has been demonstrated [38]. The extent of HLA classII antigens expression is positively correlated to the severityof chronic gastritis, as well as to the local density ofT lymphocytes and H. pylori bacteria [39]. Studies indifferent cell systems suggest that activated T cells andmacrophages modulate major histocompatibility complexclass II expression via IFN-g and TNF-a [40–44]. In

Q 1998 Blackwell Science Ltd, European Journal of Clinical Investigation, 28, 511–519

Figure 1 Increased cytokine production in H. pylori-associatedgastritis. Data were taken from Refs 1, 4–12, 14–16, 18.

Figure 2 Schematic representation of the stimulatory (þ) andinhibitory (–) effect of cytokines on recruitment and stimulationof inflammatory cells. Data were taken from Refs 1, 7, 27–31,33–35, 56.

Cytokines and peptic ulcer disease 513


H. pylori-associated gastritis, bacterial products may induceHLA-DR expression either directly or indirectly throughIFN-g or TNF-a [39].

The pathophysiological importance of epithelial HLA-DR expression in chronic type B gastritis is unknown [38].Current evidence suggests that it may induce a local over-stimulation of the B-cell system with exaggerated IgGresponses [45]. IgG antibodies can enhance the localtissue damage by activation of the complement systemand cytotoxic cells. The hypothesis that autoimmunemechanisms are involved in the pathogenesis of chronicH. pylori-associated gastritis is further supported by thefinding of cell-mediated hypersensitivity to gastric antigens[46].

H. pylori genotype and cytokine expression

H. pylori infection is extremely common throughout theworld, but only a minority of individuals develop pepticulcer disease. Several possible mechanisms have beenproposed to explain the different clinical outcome ofH. pylori infection [6]. First, host factors, i.e. mucosalcell-mediated immune mechanisms, may determine theclinical course. Second, differences among bacterial strainsmay affect the subsequent clinical outcome [6]. Approxi-mately 60% of H. pylori isolates possess a gene, cagA, whichencodes a high-molecular-weight protein (cagA protein) ofvariable size [47]. The presence of serum antibodies tocagA is strongly associated with peptic ulceration [48].Additional evidence suggests that infection with a cagAþ

strain may also increase the risk of developing gastriccancer [49,50]. The reason for this link is unknown.Infection with cagAþ strains is associated with a higherdegree of gastric inflammation and enhanced expression ofIL-1b and IL-8 [51]. The increased production of thesecytokines and the more severe mucosal inflammationinduced by cagAþ strains may explain their frequent associ-ation with peptic ulcer disease [6]. Infection with cagAþ

strains has also been associated with enhanced epithelialcell injury [48,52] that could result in accelerated mucosaldamage with loss of epithelial structure and subsequentdevelopment of atrophy and metaplasia. cagAþ strainsmight therefore initiate or promote oncogenesis viaenhanced injury to surface epithelial cells as previouslysuggested by Correa [53]. However, the association withthis genotype is only one of several factors implicated in thedevelopment of gastric cancer.

Suppression of mucosal inflammation

In addition to their proinflammatory activities, cytokinesmay have immunosuppressive properties. IL-1 and TNF-ainduce the synthesis of prostaglandins of the E type (PGE2)by smooth muscle cells and fibroblasts [1]. It is currentlyunclear whether this effect is relevant for modulating the

outcome of H. pylori-associated gastritis. PGE2 have beenshown to inhibit directly acid secretion in isolated canineparietal cells [54]. This finding is consistent with theobservation of prostaglandin-mediated inhibition of gastricacid secretion in humans [55]. Additional cytoprotectivefunctions of prostaglandins include stimulation of mucus,phosopholipid and bicarbonate secretion, enhancement ofmucosal blood flow and reduction of mucosal Hþ ion back-diffusion [54]. Further mechanisms, by which cytokinescould suppress the inflammatory process are the inhibitionof neutrophil migration by TNF-a [56], the inhibitoryeffect of IL-6 on TNF-a production [57] and the suppres-sion of lymphocyte proliferation by TGF-b [1].

Gastrin and somatostatin release

Patients infected with H. pylori have increased plasmagastrin concentrations in the basal state [58], as well asafter stimulation by meals [59–61], bombesin [62] orgastrin-releasing peptide [63]. Cure of the infection resultsin a marked fall in basal and stimulated gastrin release[58,59,64]. Gastrin stimulates the increased acid secretionin duodenal ulcer patients [65] and may be the linkbetween H. pylori infection and the occurrence of duodenalulcer disease [60].

We could demonstrate that mononuclear cells preparedfrom human peripheral blood stimulated gastrin releasefrom antral G cells [66]. Direct contact of mononuclearcells and G cells was not necessary to stimulate gastrinrelease, indicating the release of soluble factors. Threerecombinant cytokines, IFN-g, TNF-a and IL-2, but notIL-6 and IL-1b, induced gastrin release dose dependently.The stimulatory effect of TNF-a, IL-2 and IFN-g has beenconfirmed in human and rabbit antral G cells [67,68] andthe isolated intact canine antrum [69] respectively. Con-troversial data exist whether IL-8 and IL-1b stimulategastrin release or not [66,67,70]. The previously reportedstimulatory effect of LT C4 and D4 [71] has not beenexamined elsewhere (Fig. 3). Recently, we could demon-strate that not only cytokines but also H. pylori itselfstimulates gastrin release in canine antral G cells [72].

The cellular mechanisms controlling gastrin secretionhave first been studied using isolated primary G cells. Thereduced availability and viability of these cells has led to thestudy of intracellular processing at a molecular level, yield-ing more specific knowledge about the regulation of gastringene transcription. Cell lines have been developed fromgastrin-expressing tissues such as the anterior pituitary [73]and pancreatic islets [74] because no permanent antral Gcell-derived cells exist. The GH4 pituitary cell line hasfunctional receptors for several hormones controlling gas-trin secretion including epidermal growth factor (EGF)and somatostatin and allows the study of gastrin generegulation using DNA transfection techniques [75].

Gastrin gene expression is regulated by inflammation[76]. Stimulation of c-fos gene expression may be onemechanism by which inflammatory mediators activate the


gastrin promoter [76]. Several growth factors and cytokinesincluding growth EGF, platelet-derived growth factor(PDGF), TNF-a, TGF-b and IL-1 stimulate the transcrip-tional regulation of c-fos [77]. Activation of protein kinaseC (PKC) and mitogen-activated protein (MAP) kinasepathway precede c-fos gene expression [78,79]. Stimulationof the gastrin gene has been shown to correlate with anincrease in c-fos gene expression and Fos protein [76].Chronically increased Fos levels may be one of the causesof H. pylori-associated hypergastrinaemia [76].

EGF may stimulate gastrin release via luminal receptorson the apical surface of the G cell [75]. EGF has beenshown to stimulate c-fos gene expression and induce a risein Fos protein [76]. TNF-a also transiently stimulates anincrease in Fos protein, but this effect seems to be con-siderably less than with EGF [76]. The different potentialfor Fos induction may be explained by the observation thatEGF and TNF-a activate different pathways [80]. TNF-ainduces only a weak stimulation of MAP kinases Erk-1 andErk-2 but is a potent activator of c-jun gene expression andc-Jun kinases [81,82], whereas the effect of EGF seems tobe mediated in part through the MAP kinase pathway [76].

Eradication of H. pylori in infected patients results in anincreased synthesis and release of somatostatin [83]. It hasbeen suggested that suppression of somatostatin mightexplain the increased gastrin release in H. pylori-infectedpatients [83]. However, the stimulatory effect on gastrinrelease by mononuclear cells and cytokines observed in twoindependent studies [66,68] occurred in the presence of asomatostatin antibody, suggesting a direct effect on G cell-mediated gastrin release. Only one preliminary study hasexamined the effect of cytokines on somatostatin release[84]. TNF-a has been reported to have a stimulatory aswell as an inhibitory effect on somatostatin release fromcultured canine D cells. The stimulatory effect of TNF-aseemed to be enhanced by IL-8 [84].

Pepsinogen release

The human gastric mucosa contains two types of pepsino-gens, pepsinogen I, also referred to as pepsinogen A, and

pepsinogen II (pepsinogen C). Serum pepsinogen I isincreased in H. pylori-associated gastritis and duodenalulcer disease [85,86]. The increase in pepsinogen I corre-lates positively with duodenal ulcer relapse rate [87] andasymptomatic individuals with elevated pepsinogen I con-centrations are at increased risk for duodenal ulcer disease[88]. Serum pepsinogen I shows a significant fall after H.pylori eradication [87]. Intramucosal activation of pepsino-gen may be one of the reasons of mucosal injury in pepticulcer disease [89]. In addition, a rise in luminal pepsin maydegrade gastric mucus and increase the access of acid to theunderlying epithelium [90].

The mechanisms by which H. pylori affects chief cellsand mucus cells are unclear. Controversy exists regardingwhether products of the bacterium itself or cytokineslocally released by inflammatory cells stimulate pepsinogenrelease. EGF and TGF-a have been shown to stimulatepepsinogen release dose dependently in dispersed humanpeptic cells [89]. EGF receptors are expressed in differentgastric cells, including parietal and chief cells [91,92].Leukotrienes stimulate pepsinogen secretion in isolatedguinea pig chief cells [93]. It has also been demonstratedthat H. pylori itself has the potential to stimulate pepsinsecretion from isolated rabbit gastric glands [86].

Acid secretion

During the first months, infection with H. pylori is asso-ciated with hypochlorhydria [94]. This early inhibition ofgastric acid secretion may be due to the increased localproduction of TNF-a and IL-1b. IL-1b and TNF-a arepotent inhibitors of gastric acid secretion in vivo [95].Studies with isolated parietal cells suggest a direct inhibi-tion of parietal cells by TNF-a and IL-1b [96,97]. Parietalcell inhibition may involve multiple intracellular pathways,including tyrosine kinase-dependent and -independentpathways [97]. In addition, IL-1 and TNF-a-inducedsecretion of prostaglandins E2 [1] may contribute to theinhibitory effect on parietal cells [54].

Effects of cytokines on gastrointestinal motility

The relationship between H. pylori infection and gastro-duodenal motility is still controversial [98]. In H. pylori-positive patients, gastric emptying has been investigatedwith inconclusive results. Several studies have showndelayed gastric emptying in H. pylori-positive patients[99–101], whereas others failed to show a correlationwith H. pylori [102–104]. Tucci et al. [105] evenreported a higher prevalence of gastric hypomotility inH. pylori-negative patients.

Only few and conflicting data exist about manometricrecordings of interdigestive motility in H. pylori-positivepatients [106–108]. A reduced frequency of interdigestiveantral phase III of migrating motor complexes (MMC) in


Figure 3 Stimulatory effect of cytokines on gastrin release.þþEffect confirmed by human studies. þEffect confirmed by atleast one independent animal study. (þ)Controversial data ofeffect examined only in one preliminary study. Data were takenfrom Refs 66–71.



chronic H. pylori-associated gastritis has been reported[98,106], but not confirmed [108]. Qvist et al. [107]found no difference between H. pylori-positive and -negativepatients in the phase III of MMC, but normalized antro-duodenal motility after H. pylori eradication. The interpre-tation of these data has considerable limitations. First of all,the clinical significance of reduced phase III of MMC isunclear as there is a great variability in dyspeptics andnormal subjects [109–112]. Second, most studies havebeen performed on small numbers of cases and with adifferent methodological approach [98]. Third, antroduo-denal motor disorders occur in chronic gastritis, functionaldyspepsia or gastric ulcer independent of H. pylori infection[113–118].

The potential influence of cytokines on gastrointestinalmotility in H. pylori-infected patients is unknown. Animalstudies demonstrated delayed gastric emptying by IL-1b,TNF-a and IFN-g [119–126]. In the rat inhibition ofgastric motility by IL-1b has been attributed to centralmechanisms involving prostaglandin- and corticotropin-releasing factor-dependent pathways [119]. However, cur-rent evidence suggests that IL-1b modulates rat gastricmotility also through local mechanisms [120,127]. IL-1b

inhibits the in vitro motility of rat gastric smooth muscles[120] as well as jejunal, ileal and colonic smooth musclecontractions in response to acetylcholine [128]. The effectof IL-1b on gastrointestinal motility may in part bemediated by release of other cytokines, such as IL-6 orTNF [120,129,130]. TNF-a, IFN-g and IL-1b induceforestomach hypomotility in the goat [123,124] andadministration of TNF-a leads to reduced gastric motilityin the rat [125,126].

Perspectives for anticytokine treatment

Recent studies suggest that treatment of Crohn’s diseasewith anti-tumour necrosis factor antibodies is safe, effectiveand well tolerated [131–133]. The question has beenaddressed whether anticytokine treatment would also be anew treatment option for patients with peptic ulcer disease.The rationale for anticytokine treatment is a disease inwhich the available drug therapy is not effective, not longlasting or contributes to co-morbidity. We believe thatcurrently there is no role for anticytokine treatment inuncomplicated peptic ulcer disease. First of all, inflamma-tory cells and increased cytokine levels rapidly decreaseafter H. pylori eradication [13,134]. Second, the successrate for most currently used antimicrobial triple therapiesagainst H. pylori exceeds 90% and side-effects seem to betolerable for most patients. In contrast, anticytokine treat-ment may become a new treatment option for the smallgroup of ulcer patients who are unresponsive to antisecre-tory treatment and H. pylori eradication. However, beforeanticytokine treatment can be applied, further evidence isneeded to learn which cytokine is the single most importantfor peptic ulcer development. In comparison, in patientswith Crohn’s disease TNF-a is not only increased in the

mucosa [131,132] but is also believed to play a central rolein the pathogenesis [132,133]. In addition, neutralizationof TNF has been demonstrated to decrease recruitment ofinflammatory cells and granuloma formation in differentanimal models [131].

Conclusions

H. pylori is the cause of chronic type B gastritis and occursin almost all patients with duodenal ulcer disease. How-ever, clinical disease occurs in fewer than 20% of allH. pylori-infected subjects [2]. Several hypotheses includ-ing strain differences and host factors have been suggestedto explain the different consequences of H. pylori infection.H. pylori isolates have a considerable genotypic and pheno-typic diversity [6]. The presence of cagA, vacA s1a andpossibly picA and picB are significant risk factors for pepticulceration [6,135]. Other genetic markers of pathogenicitywill certainly be found because the whole genome sequenceof H. pylori has been analysed [136]. Current evidencesuggests that virulence factors for peptic ulcer disease areassociated with enhanced gastric inflammation [6,135]. Wespeculate that their high ulcerogenic potential is mediatedin part by increased activity of one or several key cytokineswith IL-8 or TNF-a as the most attractive candidates. Bothin vitro and in vivo studies are necessary to test thishypothesis. From a methodological standpoint the mostfocused study would be a controlled comparison of pepticulcer patients, who are treated either with antisecretorydrugs and antibiotics for H. pylori eradication (group I) orwith antisecretory drugs only (group II). In both groups thetime course of cytokine expression would have to bedetermined by serial gastric biopsies. We speculate that ingroup II patients, IL-8 and TNF-a would show increasedtissue levels until ulcer relapse. In comparison, gastricinflammation and increased cytokine expression areknown to decrease after H. pylori eradication [13,134].However, the consent of patients to such a study is dubiousbecause of the high ulcer recurrence rate without H. pyloritreatment.

Recently, it has been demonstrated that cagAþ com-pared with cagA– strains have elevated antral IL-8 proteinlevels [6]. Similarly, the cytokine pattern induced by vacAs1a strains needs to be examined because this strain seemsto be correlated with more gastric inflammation and ahigher prevalence of peptic ulcer than s1b or s2 strains[135]. Other genetic markers of high ulcerogenic potentialwill certainly be found in the near future and in vitro studieswill determine whether they induce the same cytokinepattern as cagAþ and vacA s1a strains.

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Hypotheses on the role of cytokines in peptic ulcer disease