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Inflammatory bowel disease is characterized by dysregulated immune responses in inflamed intestine, with dominance of interleukin-17 ( IL-17) -producing cells and deficiency of regulatory T (Treg) cells. The aim of this study was to investigate the effect and mechanisms of sirolimus, an inhibitor of the mammalian target of rapamycin, on immune responses in a murine model of Crohn's disease. Murine colitis was induced by intrarectal administration of 2,4,6-trinitrobenzene sulphonic acid at day 0. Mice were then treated intraperitoneally with sirolimus daily for 3 days. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. Sirolimus treatment significantly decreased all macroscopic, microscopic and histopathological parameters of colitis that were analysed. The therapeutic effects of sirolimus were associated with a down-regulation of pro-inflammatory cytokines tumour necrosis factor-α, IL-6 and IL-17A. Intriguingly, sirolimus administration resulted in a prominent up-regulation of the regulatory cytokine transforming growth factor-β. Supporting the hypothesis that sirolimus directly affects the functional activity of CD4+ CD25+ Treg cells, we observed a remarkable enhancement of FoxP3 expression in colon tissues and isolated CD4+ T cells of sirolimus-treated mice. Simultaneously, sirolimus treatment led to a significant reduction in the number of CD4+ IL-17A+ T cells in the mesenteric lymph node cells as well as IL-17A production in mesenteric lymph node cells. Therefore, sirolimus may offer a promising new therapeutic strategy for the treatment of inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examined the role of IL-33 in mucosal healing and epithelial restoration and repair. [•] The expression of IL-33 is enhanced in incisional wound skin. [•] Administration of exogenous IL-33 accelerates wound healing. [•] IL-33 promotes collagen deposition and ECM synthesis. [•] The effect of IL-33 is associated with upregulation of alternatively activated macrophages (AAM). [ABSTRACT FROM AUTHOR]

Abstract: Although studies have shown that heme oxygenase-1 (HO-1) can abrogate leukocyte recruitment and tissue injury after LPS stimulation, the underlying mechanisms remain incompletely understood. Interleukin (IL)-33, a new member of the IL-1 family, is found to play a crucial immunoregulatory effect on the MD2/TLR4 complex expression. Moreover, TLR4 further promotes the activation of NF-κB and the production of proinflammatory mediators, which exacerbate neutrophil infiltration and organ damage. The present study was designed to determine whether the protection of HO-1 against LPS-induced acute lung injury (ALI) is involved in downregulation of IL-33. We observed that the levels of IL-33 mRNA and protein in LPS-stimulated macrophages were strongly suppressed by a potent HO-1 inducer, CoPP, treatment. Meanwhile, CoPP significantly reduced the expression of TLR4 and TNF-α in IL-33-pretreated macrophages followed LPS challenge. In the murine model of LPS-induced ALI, CoPP treatment resulted in a remarkable decrease in LPS-mediated leukocyte exudation, Evans blue dye albumin (EBA) leakage as well as histopathologic disruption. Notably, CoPP treatment markedly inhibited the expression of IL-33 and TLR4 in lung tissues under LPS stimulation. Therefore, these data suggest that the cytoprotection of HO-1 in LPS-induced pulmonary injury is associated with negative regulation of IL-33 and TLR4-mediated inflammatory response. [Copyright &y& Elsevier]

Abstract: Although studies have demonstrated that heme oxygenase-1 (HO-1) prevents leukocyte infiltration and organ damage following LPS challenge, the mechanisms involved in this protection are incompletely understood. Macrophage migration inhibitory factor (MIF) is thought to play a pivotal role in modulation of inflammatory and immune response through upregulation of TLR4 expression. Activation of TLR4 results in the production of proinflammatory mediators including MIF, which induce neutrophils recruitment and subsequent tissue insults. We hypothesized that HO-1 mediates its salutary effects in lipopolysaccharide (LPS)-induced inflammatory lung injury via downregulation of MIF through modulation of TLR4-induced proinflammatory mediator production. Compared with wild-type cells, MIF-knockdown macrophages in vitro are hyporesponsive to LPS stimulation, as shown by a profound reduction in TLR4 expression and TNF-α production. In the murine model of LPS-induced acute lung injury, administration of CoPP, a potent HO-1 inducer, leaded to a significant reduction in LPS-induced pulmonary edema, leucocytes influx, myeloperoxidase activity as well as histopathologic insults. Most strikingly, pretreatment with CoPP markedly decreased the expression of TLR4 and MIF in lung tissues in response to LPS challenge. These findings herein suggest that the cytoprotective functions of HO-1 in LPS-induced lung injury are associated with negative regulation of lung MIF and TLR4-induced inflammatory response. [ABSTRACT FROM AUTHOR]