A Novel Role for Defensins in Intestinal Homeostasis: Regulation of IL-1β Secretion

Abstract

Impaired expression of α-defensin antimicrobial peptides and overproduction of the proinflammatory cytokine IL-1β have been associated with inflammatory bowel disease. In this study, we examine the interactions between α-defensins and IL-1β and the role of defensin deficiency in the pathogenesis of inflammatory bowel disease. It was found that matrix metalloproteinase-7-deficient (MMP-7−/−) mice, which produce procryptdins but not mature cryptdins (α-defensins) in the intestine, were more susceptible to dextran sulfate sodium-induced colitis. Furthermore, both baseline and dextran sulfate sodium-induced IL-1β production in the intestine were significantly up-regulated in MMP-7−/− mice compared with that in control C57BL/6 mice. To elucidate the molecular mechanism for the increased IL-1β production in defensin deficiency in vivo, we evaluated the effect of defensins on IL-1β posttranslational processing and release. It was found that α-defensins, including mouse Paneth cell defensins cryptdin-3 and cryptdin-4, human neutrophil defensin HNP-1, and human Paneth cell defensin HD-5, blocked the release of IL-1β from LPS-activated monocytes, whereas TNF-α expression and release were not affected. Unlike α-defensins, human β-defensins and mouse procryptdins do not have any effect on IL-1β processing and release. Thus, α-defensins may play an important role in intestinal homeostasis by controlling the production of IL-1β.

Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

“…So although they clearly disable the macrophage protein translation machinery, they do not induce macrophage apoptosis (5). A previous study reported that α-defensins reduced the release of IL-1β from activated monocytes, while not affecting the transcription of IL-1β mRNA (28). Based on our findings, these observations can likely be explained by the translation of pro-IL-1β being impaired.…”

“…5 and 6), and the polysomal distribution of these mRNAs was similar in control and HNP1-treated RRL and HMDMs. Translational repression could be occurring via either elongation and/or termination (27), and we would speculate that HNP1 prevents translation elongation (22), which has recently been established as a major control point for protein synthesis (28).…”

A rat model of mild intestinal inflammation induced byStaphylococcus aureusenterotoxin B

“…In the rat model, SEB reduced the expression of a-defensin cryptdin 4 and b-defensin 1 (41) . Since cryptdin 4 can block IL-1b release from lipopolysaccharide-activated monocytes (42) , a decrease in its expression may increase intestinal IL-1b production. This would make the intestine more susceptible to SEB-induced damage and contribute to inflammatory bowel diseases (41) .…”

Defensins: Potential Effectors in Autoimmune Rheumatic Disorders

“…For instance, monocytes (Mo), macrophages (MΦ) and immature dendritic cells (iDC) are attracted to sites of inflammation by defensins [12][13][14][15][16], where the secretion of proinflammatory cytokines by these cells is modulated, although there is still dispute to whether HNP1-3 are predominantly pro- [17,18] or anti-inflammatory [19][20][21]. Moreover, defensins have an impact on antigen presentation by influencing processes of differentiation: HNP1-3 was shown to inhibit M-CSF induced macrophage differentiation of monocytes [22], while maturation of iDC with upregulation of the co-stimulatory molecules CD80 and CD86 as well as MHCII is promoted by hBD3 [5,12,23].…”