TNF Receptor Type I-Dependent Activation of Innate Responses to Reduce Intestinal Damage-Associated Mortality

Inflammatory cytokines mediate inflammatory bowel diseases (IBDs) and cytokine blocking therapies often ameliorate the disease severity. IL-32 affects inflammation by increasing the production of IL-1, TNFα, and several chemokines. Here, we investigated the role of IL-32 in intestinal inflammation by generating a transgenic (TG) mouse expressing human IL-32γ (IL-32γ TG). Although IL-32γ TG mice are healthy, constitutive serum and colonic tissue levels of TNFα are elevated. Compared with wild-type (WT) mice, IL-32γ TG mice exhibited a modestly exacerbated acute inflammation early following the initiation of dextran sodium sulfate (DSS)-induced colitis. However, after 6 d, there was less colonic inflammation, reduced tissue loss, and improved survival rate compared with WT mice. Associated with attenuated tissue damage, colonic levels of TNFα and IL-6 were significantly reduced in the IL-32γ TG mice whereas IL-10 was elevated. Cultured colon explants from IL-32γ TG mice secreted higher levels of IL-10 compared with WT mice and lower levels of TNFα and IL-6. Constitutive levels of IL-32γ itself in colonic tissues were significantly lower following DSS colitis. Although the highest level of serum IL-32γ occurred on day 3 of colitis, IL-32 was below constitutive levels on day 9. The ability of IL-32γ to increase constitutive IL-10 likely reduces TNFα, IL-6, and IL-32 itself accounting for less inflammation. In humans with ulcerative colitis (UC), serum IL-32 is elevated and colonic biopsies contain IL-32 in inflamed tissues but not in uninvolved tissues. Thus IL-32γ emerges as an example of how innate inflammation worsens as well as protects intestinal integrity.

Section: Protective Role For Tnfα In the Innate Response Of The Intesmentioning

confidence: 70%

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Choi

Bae

Hong

et al. 2010

“…Activation of NF-κB is similarly protective for the development of systemic inflammation, but not for the prevention of local injury to the mucosa in an animal model of intestinal ischemia-reperfusion (18). Finally, the observations that TNF-α-deficient mice or mice deficient in TNFRI signaling in the intestinal epithelium are more susceptible to DSS acute colitis strongly support the concept that TNF-α may exert protective functions in normal gut homeostasis and intestinal epithelial integrity (19,20). Altogether, these observations suggest that the beneficial effects of probiotics are associated with immunostimulatory effects rather than immunosuppression.…”

Section: Discussionmentioning

confidence: 94%

Probiotics promote gut health through stimulation of epithelial innate immunity

Pagnini

Saeed

Bamias

et al. 2009

302

223

Probiotic formulations are widely available and have a variety of proposed beneficial effects, including promotion of gut health. The mechanisms of action of probiotic bacteria in the intestine are still unclear but are generally attributed to an antiinflammatory effect. Here, we demonstrate that the multiple probiotic formulation VSL#3 prevents the onset of intestinal inflammation by local stimulation of epithelial innate immune responses (i.e., increased production of epithelial-derived TNF-α and restoration of epithelial barrier function in vivo). We also demonstrate that probiotic bacteria stimulate epithelial production of TNF-α and activate NF-κB in vitro. Our results support the hypothesis that probiotics promote gut health through stimulation, rather than suppression, of the innate immune system. Furthermore, our findings provide the perspective that defects in innate immunity may play a critical role in the pathogenesis and progression of intestinal disorders, such as inflammatory bowel disease.

“…Moreover, Tnf −/− mice challenged with DSS have enhanced inflammation and colonic epithelial damage in the colon and succumb to DSS-induced colitis (28,29). Therefore, we questioned whether IL-23 in the presence or absence of TNF-α signals could induce IL-22 production by colonic granulocytes and/or macrophages.…”

Section: Il-22 Levelsmentioning

confidence: 99%

IL-22–producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis

Zindl

Lai

Lee

et al. 2013

303

271

IL-22 plays an important role in mucosal epithelial cell homeostasis. Using a dextran sodium sulfate-induced mouse model of acute colitis, we observed an IL-23-dependent up-regulation of IL-22 in the middle and distal colon at the onset of epithelial cell damage. This heightened IL-22 correlated with an influx of innate immune cells, suggesting an important role in colonic epithelial protection. Freshly isolated colon-infiltrating neutrophils produced IL-22 contingent upon IL-23 signaling, and IL-22 production was augmented by TNF-α. Importantly, the depletion of neutrophils resulted in diminished IL-22 levels in the colon, and the transfer of IL-22-competent neutrophils to Il22a-deficient mice protected the colonic epithelium from dextran sodium sulfate-induced damage. In addition, IL-22-producing neutrophils targeted colonic epithelial cells to up-regulate the antimicrobial peptides, RegIIIβ and S100A8. This study establishes a role for neutrophils in providing IL-22-dependent mucosal epithelial support that contributes to the resolution of colitis.interleukin-22 | intestinal inflammation | leukocytes