Immunoregulatory Role of Contra-inflammatory Cytokines in Inflammatory Bowel Disease

  • S. Schreiber
  • A. Raedler
Conference paper

Summary

Background. In inflammatory bowel disease peripheral monocytes and intestinal macrophages exhibit an increased state of priming and activation. The enhanced state of activation results in an increased capacity to secrete pro-inflammatory mediators (lipid autacoids and pro-inflammatory cytokines) and also non-specific toxic molecules (i.e. Superoxide anions or nitric oxide) in vitro and in vivo. Contrainflammatory mechanisms, in particular downregulating cytokines, may be of great importance in limiting the pro-inflammatory potential of activated mononuclear phagocytes. Our hypothesis is that the response of IBD mononuclear phagocytes to some of the downregulating factors, particularly Interleukin 4 (Il-4), may be altered.

Methods. Peripheral monocytes from IBD patients and normal controls were isolated by serial density centrifugations, intestinal lamina propria mononuclear cells (LPMNC) by collagenase digestion. The secretion of pro-inflammatory cytokines (Il-1β, TNF-α, Il-1-ra) into culture supernatants was assessed by ELISA. In parallel, Superoxide anion release, macrophage mannose receptor, and monocyte Il-4 receptor expression were assessed. The immunoregulatory role of contra-inflammatory mediators (prostaglandin E2 (PGE2), Il-4, Il-10, Il13) on the release of pro-inflammatory molecules was in vestigated.

Results. Our findings confirm that IBD peripheral monocytes and intestinal macrophages show an enhanced capacity to secrete pro-inflammatory cytokines (Il-1β, TNF-α) and also non-specific effector molecules like Superoxide anions in comparison with normal controls. Secretion of the anti-inflammatory molecule Il-1 receptor antagonist (Il-1-ra) by IBD monocytes is not increased, which leads to a preponderance of pro-inflammatory Il-1β over the receptor antagonist in IBD. As we find that Il-4 is effectively down-regulating pro-inflammatory cytokine (Il-1β, TNF-α) and Superoxide anion secretion by resting as well as LPS-activated normal monocytes we also find that IBD peripheral monocytes show a diminished responsiveness to the inhibitory effect of Il-4. In vitro maturation did not change the altered response pattern of IBD monocytes to Il-4. Moreover, an impaired down-regulation of TNF-α secretion by Il-4 could also be found in IBD intestinal LPMNC which was similar to that seen in peripheral monocytes. The Il-1-ra/Il-1β ratio is increased by Il-4 treatment of normal monocytes, whereas in IBD monocytes the persistence of low Il-1-ra/Il-1β ratios after Il-4 stimulation demonstrates that Il-1β secretion still prevails over Il-1-ra. To further characterize the complex immunoregulatory properties of Il-4, we studied its ability to induce expression of the macrophage mannose receptor, which is a molecule pivotal to macrophage mediated host defense by binding high mannose glycoproteins on pathogens. Il-4 is a potent inducer of the mannose receptor on normal monocytes whereas the responsivity of IBD monocytes is impaired. In monocytes from disease specificity controls (colonic diverticulitis, bacterial pneumonia) no impairment of the Il-4 regulation was seen. No impaired down regulation of activation by Il-10 or PGE2 was seen in IBD mononuclear phagocytes.

Conclusions. Interleukin 4 mediated down-regulation of pro-inflammatory molecules secreted by mononuclear phagocytes is disturbed in IBD.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • S. Schreiber
  • A. Raedler

There are no affiliations available

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