Cytokines In Inflammatory Bowel Disease Research Articles

Mucosal repair by growth factors and anti-inflammatory cytokines in inflammatory bowel disease

Mucosal repair by growth factors and anti-inflammatory cytokines in inflammatory bowel disease

Mucosal repair by growth factors and anti-inflammatory cytokines in inflammatory bowel disease

Mucosal repair by growth factors and anti-inflammatory cytokines in inflammatory bowel disease

Increased expression of IL-16 in inflammatory bowel disease

BACKGROUND Inflammatory bowel disease (IBD) is characterised by infiltration of inflamed mucosal regions with CD4+ T lymphocytes and other mononuclear cells. Interleukin (IL)-16 exerts a strong chemoattractant activity on CD4+...

Invited review: Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance

Ulcerative colitis (UC) and Crohn's disease (CD) [inflammatory bowel disease (IBD)] are both characterized by an exaggerated immune response at the gut associated lymphoreticular tissue level. Such an abnormal and dysregulated immune response may be directed against luminal and/or enteric bacterial antigens, as also supported by murine models of inflammatory bowel disease (IBD) caused by organisms such as Citrobacter rodentium and Helicobacter hepaticus. Bacterial endotoxins or lipopolysaccharides (LPS) have been detected in the plasma of IBD patients and an abnormal microflora and/or an increased permeability of the intestinal mucosa have been invoked as cofactors responsible for endotoxemia. At the same time, the evidence that phagocytosis and killing exerted by polymorphonuclear cells and monocytes and the T-cell dependent antibacterial activity are decreased in IBD patients may also explain the origin of LPS in these diseases. In IBD, pro-inflammatory cytokines and chemokines have been detected in elevated amounts in mucosal tissue and/or in peripheral blood, thus suggesting a monocyte/macrophage stimulation by enteric bacteria and/or their constituents (e.g. LPS). On these grounds, in experimental models and in human IBD, anti-cytokine monoclonal antibodies and interleukin receptor antagonists are under investigation for their capacity to neutralize the noxious effects of immune mediators. Finally, the administration of lactobacilli is beneficial in human IBD and, in murine colitis, this treatment leads to a normalization of intestinal flora, reducing the number of colonic mucosal adherent and translocated bacteria.

High doses of azathioprine but not 6-mercaptopurine inhibit the production of pro-inflammatory cytokines in inflammatory bowel diseases: An in vitro study

High doses of azathioprine but not 6-mercaptopurine inhibit the production of pro-inflammatory cytokines in inflammatory bowel diseases: An in vitro study

Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance

Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance

Chemokines and cytokines in inflammatory bowel disease and their application to disease treatment

The term inflammatory bowel disease refers to two chronic, relapsing or remitting, inflammatory disorders of the intestinal tract that although somewhat similar clinically represent two markedly different and distinct disorders histologically, endoscopically, immunologically, and by many other means. The pathogenesis of these diseases, ulcerative colitis and Crohn's disease, remains unknown and medical and surgical therapy is limited. Approximately 70% of individuals with Crohn's disease require surgery with another 40% to 45% requiring reoperation, whereas approximately 20% to 25% of patients with ulcerative colitis undergo surgical intervention. This review highlights the specific clinical features of the disease as well as some of the recent insights into the cause of the disease. Standard medical therapy is highlighted and more recent biologic therapies including the use of anti-tumor necrosis factor-alpha antibodies are described. The changing focus of therapy from nonspecific anti-inflammatory medications to targeted biologic therapies is reviewed. A number of novel therapeutic targets are highlighted and future directions for research and clinical testing are discussed.

Cytokine-targeted therapeutic approaches for inflammatory bowel disease

Although the causes of inflammatory bowel disease currently are not fully understood, increasing evidence implicates cytokines as key factors in the development of this disorder. The rationale for cytokine-targeted therapy for inflammatory bowel disease has been refined significantly and clinical studies have been initiated. Efficacy of therapy with antitumor necrosis factor-alpha antibody has already been established and clinical trials of recombinant interleukin-10 and interleukin-11 are in progress. Recent investigations have also focused on intracellular signaling pathways and transcription factors that regulate production and activation of cytokines. Further elucidation of the immune response and the role of cytokines in inflammatory bowel disease may lead to identification of additional possible targets for therapeutic intervention that could improve management of the disease.

T-cell cytokines in inflammatory bowel disease: intracellular detection of cytokines using flow cytometry

t~tiology of inflammatory bowel disease is still unknown. There are several hints speaking for an immunological background. We wanted to investigated this Thl / Th2 hypothesis for the respective types of colitis in IBD patients.We therefore investigated T-cell cytokines in peripheral blood mononuclear cells (PBMC) and lamina propria mononuclaer ceils (LPMC) from 6 Crohn' disease (CD), 6 ulcerative colitis(UC) patients and 10 healthy controls. PBMC were isolated using standard procedures, then stimulated for five hours with PMA and ionomycin. The ceils were fixed in 4% paraformaldehyd, then lysed in saponin-buffer. Anti-cytokine antibodies and antibodies to surface markers were added at the same time. Cells were finally measured in the FACS. Cytokines of interest were interferon (IFN)r, interleukin (IL) 2 and tumor necrosis factor (TNF) a as Thl cytokines and IL4, IL5 and IL 10 as Th2 cytokines. For staining of surface markers we used CD3 (T-cells), CD8 (cytotoxic T-cells, CD8neg helper T-cells), CD45RA and CD45R0 for naive and memory cells, respectively. As to surface markers, ratio of CD8pos/CD8neg T-cells was not different between PBMC and LPMC. PBMC mainly revealed the naive phenotype (CD45RApos) whereas these cells were greatly decreased in LPMC which mainly displayed the memory phenotype (CD45R0pos). CD45RA pos cells were significantly increased in UC mucosa when compared to controls and CD patients. All measured cytokines were produced to greater extends in memory cells than in naive cells. IL2 was the main cytokine produced in PBMC and reduced in LPMC. It was produced primarily in CD8 neg cells. IL2 production was significantly reduced in CD45RApos and CD8 pos cells in UC mucosa. IFNr was the main cytokine produced in mucosal cells and percentages of positive cells were always higher than in PBMC, it was produced to similar amounts in CDSpos and CD8neg cells. IN LPMC, CD patients produced highest amounts of IFNr, controls intermediate amounts and UC showed weakest production. Th2 cytokines were produced by very few cells, we did not find any differences between LPMC and PBMC nor between disease groups. IL4 was produced to some higher extents than IL5 and IL 10. In our investigations we could find interesting differences between mucosal and blood derived lymphocytes. As to comparison of disease groups, CD patients showed highest amounts of IFNr production and reduction in IL4 which supports the Thl hypothesis.

Are mononuclear cells the site of action of steroids & “anti-inflammatory” cytokines in colitis?

Are mononuclear cells the site of action of steroids & “anti-inflammatory” cytokines in colitis?

Mucosal expression of interleukin-6 and interleukin-8 messenger RNA in ulcerative colitis and in Crohn's disease.

To elucidate the possible role of proinflammatory cytokines in inflammatory bowel disease, the expression and localization of interleukin (IL) -6 and IL-8 mRNAs were examined in colonic biopsy specimens obtained from 10 patients with active ulcerative colitis (UC), 5 with inactive UC, 6 with Crohn's disease (CD), and 5 normal controls. In situ hybridization with digoxigenin-labeled probes and immunohistochemistry for both cytokines were performed. The IL-6 mRNA expression was enhanced in the inflamed mucosa in 4 of 6 CD patients, while that of UC patients stayed at baseline. In contrast, IL-8 mRNA expression was apparently augmented (P = 0.044) in 7 of 10 active UC and 3 of 6 CD patients (NS). The cell count positive for IL-8 mRNA per unit area was definitely increased in moderate/severe UC when compared to mild UC (53.1 +/- 14.4/mm2 vs 9.0 +/- 5.1/mm2, P = 0.028) according to the degree of inflammation. IL-6 mRNA positive cells in CD were preferentially located in deeper lamina propria than IL-8 mRNA positive cells in UC. Interestingly, IL-8 mRNA was expressed in the mucosal epithelial cells in one UC patient. The patients treated by corticosteroids tended to show suppressed expression of each mRNA, except one patient with intractable UC. Our data suggest enhanced expression of mucosal IL-6 mRNA in CD and of IL-8 mRNA in UC by infiltrating mononuclear cells, indicating the distinct participation of each cytokine in the pathogenesis of UC and CD. Moreover, intestinal epithelial cells in UC occasionally exhibit IL-8 mRNA.

Cytokines in inflammatory bowel disease

Over the past decade, much has been learned regarding the role of various cytokines in the pathogenesis of inflammatory bowel disease. Several cytokine ‘knockout’ models in mice have been shown to develop colitis, while alterations in the production of various cytokines has been documented in human Crohn's disease and ulcerative colitis. In recent years, attempts have been made to treat these diseases through modulation of cytokine production or action. This review focuses on the cytokines that have been implicated in the pathogenesis of inflammatory bowel disease. The evidence for and against a role for particular cytokines in intestinal inflammation is reviewed, as is the experimental and clinical data suggesting that cytokines are rational targets for the development of new therapies.

Pro-inflammatory cytokines in inflammatory bowel disease.

Pro-inflammatory cytokines in inflammatory bowel disease.

Regulatory cytokines in inflammatory bowel disease.

Several immunological alterations have been described in inflammatory bowel disease, but their role in the pathogenesis of tissue damage of these disorders is not fully known. Activated immune cells produce proinflammatory and regulatory cytokines able to mediate immune mechanisms underlying intestinal inflammation in both ulcerative colitis and Crohn's disease. Although there is no evidence for an aberrant cytokine secretion in the intestinal mucosa of patients with inflammatory bowel disease, observations seem to indicate that locally released cytokines trigger the preferential differentiation of mucosal lymphocytes into TH1 or TH2 subsets. The unresponsiveness of intestinal mononuclear cells to the inhibiting effects of regulatory cytokines may, also, contribute to this differentiation.

Intestinal cytokines in inflammatory bowel disease and invasive diarrhoea

In the intestine large numbers of bacteria and their products are separated by a single epithelial layer from resident inflammatory cells (macrophages and lymphocytes). Many of these bacterial products, such as lipopolysaccharides and peptidoglycans, are potent stimulators of free radical and inflammatory cytokine production by macrophages. This can occur in vivo in response to mucosal invasion by enteropathogenic bacteria or because of inappropriate activation of these cells, as in chronic inflammatory bowel disease. In this review we present evidence for production of cytokines in normal intestine and in intestinal inflammatory conditions. The adverse effects of cytokine production upon intestinal homeostasis, in particular disruption of epithelial integrity and prothrombotic changes in the vascular endothelium, are also discussed.

The Role of Cytokines in Inflammatory Bowel Disease

Cytokines play an important role in the development and persistence of the inflammatory lesions seen in Crohn's disease and ulcerative colitis. This review discusses the current thinking of the role of cytokines in chronic intestinal inflammation including the involvement of immunoregulatory cytokines within the Th1 and Th2 subsets.

Cytokine Induction in Experimental and Ulcerative Colitis

In order to delineate the role of cytokines in inflammatory bowel disease, we studied induction of these mediators in an acetic acid-induced rat model for colitis. In this model, IL-1β mRNA induction was detected early after induction of acute colitis. Using in situ hybridization techniques, enterocytes were identified as the predominant source of IL-1β mRNA. TNFα mRNA was detected with in situ hybridization in cells located in the lamina propria and in the submucosa. Immunofluorescent techniques showed cells with the same localisation producing TNFα protein. Cultured human colon biopsies from patients with ulcerative colitis secreted large amounts of interleukin-1 but only modest quantities of tumor necrosis factor. Thus, interleukin-1 is synthesized in experimental as well as ulcerative colitis, and may be causally related to its pathogenesis. These findings open new possibilities for development of intervention strategies in ulcerative colitis.

Pathogenetic and clinical relevance of cytokines in inflammatory bowel disease

Cytokines appear to be integrally involved in the pathogenesis of IBD through their immunoregulatory and effector activities. This pathway will provide new opportunities for specific pharmacologic intervention with limited toxicity and may yield sensitive objective markers of disease activity. Hopefully, determining and comparing profiles of cytokines in tissues of normals, acute self-limited colitis, and active and inactive phases of IBD will permit a clearer understanding of the disordered immunoregulation leading to the unrestrained inflammatory response of IBD.