Expression of IL‐18 in intestinal epithelial cells (IEC) has been implicated in Th1 cell‐mediated chronic intestinal inflammation and anti‐tumor immunity. However, physiological regulatory factors have not been identified. Besides their effects on proliferation and restitution, immunomodulatory functions have been attributed to short chain fatty acids (SCFA). We investigated the effect of SCFA (butyrate, propionate, acetate) on expression of IL‐18 in IEC in vitro and in vivo. Expression of IL‐18 mRNA and protein in human carcinoma‐derived HT‐29 and Caco‐2 cells was analyzed by reverse transcription‐PCR and Western blot. Transcriptional regulation of IL‐18 gene expression was determined by transient transfection of wild‐type and mutated IL‐18 promoter. Further, in vivo expression of IL‐18 in the intestine from butyrate‐treated and untreated mice was assessed by immunohistochemistry. IL‐18 mRNA and the IL‐18 protein were expressed in IEC, while IL‐18 secretion was not observed. Butyrate and acetate increased intracellular IL‐18 content in a time‐ and dose‐dependent fashion. In contrast to proinflammatory stimuli butyrate potently activated the IL‐18 promoter, indicating that IL‐18 is regulated at the transcriptional level by SCFA. Furthermore, a 108‐bp sequence in the proximal region was identified to be essential for IL‐18 promoter activation by butyrate. As proof of principle butyrate effects were confirmed in vivo by demonstration of increased IL‐18 protein expression in IEC from butyrate‐treated mice. In conclusion, SCFAup‐regulate IL‐18 protein expression in IEC, suggesting a potential regulatory contribution of these luminal constituents to T cell mediated inflammatory and neoplastic intestinal conditions.
Leptin can regulate several immune functions. However, the role of leptin on lymphocyte function has not been recognized in vivo. Accordingly, we have investigated the effect of leptin on starvation-induced immune dysfunction using diet-induced obese mice. To induce obesity, C57BL/6J mice were fed a high-fat diet for 14 weeks and control mice were fed a standard diet for the same period. The obese and control groups of mice were then starved for 48 h, and received intraperitoneal injections of recombinant leptin or phosphate-buffered saline four times during starvation. Other control mice in both diet groups were free fed without being starved. Although starvation of the control mice dramatically reduced the weights of the immune organs, cytokine production and increased proliferation of cultured splenocytes, these levels returned to those of the free-feeding groups with exogenous leptin administration. However, these effects of leptin were not observed in obese mice. These findings provide some evidence that leptin can regulate the immune function in vivo. It is also suggested that the action of leptin might not appear in obesity.
Objective: To understand the effect of obesity and insulin on immune functions in non-insulin-dependent diabetes mellitus (NIDDM). Subject: Fourteen obese NIDDM (body mass index (BMI) ¼ 30.6 AE 1.1), seven non-obese NIDDM (BMI ¼ 24.2 AE 0.5) and five obese non-NIDDM (BMI ¼ 28.3 AE 0.67). Interventions: We first examined the influence of insulin on the proliferation of several human cell lines. Second, we compared several immune functions between obese and non-obese NIDDM, and obese non-NIDDM patients using peripheral blood mononuclear cells. Result: Insulin decreased proliferation of T-cell lines but not that of other types of cell lines. Furthermore, obesity augmented the production of IL-1b which could have cytotoxity against islet b cells in NIDDM. Conclusion: Our data suggested that the pathophysiology of NIDDM could be affected by the change of immunity due to obesity, and the treatment of obesity in NIDDM may be important from an immunological aspect.
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