SUMMARYNeuroendocrine peptides have a variety of physiological functions in the gastrointestinal tract. This study was carried out to investigate the impact of IL-2 deficiency on the neuroendocrine system in normal colon, and the neuroendocrine changes during colonic inflammation. Mice with homozygous disrupted IL-2 gene (IL-2 2/± ) spontaneously developed a bowel disease with similarities to human ulcerative colitis. Different types of colonic endocrine cells and myenteric nerves were analysed in the IL-2 2/± mice using immunomorphometry. The neuropeptide contents in the colonic tissues were determined by radioimmunoassay. Age-matched healthy IL-2 1/± and IL-2 1/1 mice served as controls and the colonic IL-2 levels were compared between these two groups of mice by ELISA. Our data showed that less than half the amount of IL-2 was synthesized in the colon of IL-2 1/± mice compared with the IL-2 1/1 wild-type mice. Two major differences in the neuroendocrine colon were found between the mice with an intact and disrupted IL-2 gene. One was age-related. The frequencies of various endocrine cells and myenteric nerves increased with age in the IL-2 1/1 mice. However, no such increases were seen in the mice with a disrupted IL-2 gene. Instead, the volume densities of enteroglucagon, serotonin cells and substance P (SP), vasoactive intestinal polypeptide (VIP) and total myenteric nerves were lower in the older IL-2 1/± and IL-2 2/± mice compared with the wild type. The other was disease-related. Polypeptide YY (PYY) cells and tissue levels of PYY, SP and VIP were significantly decreased in the IL-2 2/± mice during the course of bowel inflammation compared with the healthy IL-2 1/± and IL-2 1/1 controls. These findings indicate that colonic neuroendocrine alterations did occur in the mice with a disrupted IL-2 gene and diminished local IL-2 level, suggesting a role of IL-2 in the regulation of the neuroendocrine system and a prevalent interaction between the immune and neuroendocrine systems in normal colon. On the other hand, there were some changes that seemed to correlate with the bowel inflammatory process. They might be associated with the impaired function in inflamed gut and contribute to the development and/or prolongation of disease.

Substance P (SP), one of the most prevalent neuropeptides in gut, has been reported to have potent immune modulatory effects as a proinflammatory agent. The synthesis of SP and SP receptor expression in intraepithelial and lamina propria T lymphocytes of mouse intestine was investigated. Using RT-PCR analysis, it was demonstrated that SP receptor mRNA was exclusively expressed in intraepithelial and lamina propria T lymphocytes as well as their purified CD4+, CD8+ and CD4–CD8–CD3+ subsets. Messenger RNAs (mRNAs) for the two precursors of SP, β and γ-preprotachykinin-A, were also detected. These results were consistent in lymphocytes from both epithelium and lamina propria of small and large intestines, although the frequencies and/or intensities of mRNA expression varied. However, none of the findings could be repeated in splenic T lymphocytes. Activation of splenocytes with anti-CD3Ε-chain mAb and PMA did not induce expression of SP or its receptor mRNAs. Furthermore, both cytoplasmic and surface-bound SP was demonstrated in intestinal T lymphocytes using dual color immunocytochemistry and immunoflow cytometry. In vitro treatment with SP did not significantly change the size of the SP-immunoreactive T cell population, indicating the presence of SP receptor on intestinal T lymphocytes as well as in vivo binding of endogenously released SP. Our data suggest that SP production and SP receptor expression are distinctive for mouse intestinal mucosal immunity and that SP may act as a modulator of an ongoing controlled inflammation in normal gut, by acting through its specific receptor on T lymphocytes in an autocrine and/or paracrine pattern.

SummaryMice homozygous for an inactivation of the interleukin-2 (IL-2) gene develop a T-cell dependent colitis. Heterozygous (IL-2 +/--) mice are clinically healthy but have been shown to express reduced levels of IL-2 in the colon. Splenocytes from the IL-2 +/--mice had a poorer proliferative response to polyclonal T-cell activation and these mice have reduced numbers of intestinal regulatory T cells (CD4 + CD25 + cells) when compared to wild type mice. When exposed to dextran sulphate sodium (DSS) IL-2 +/--mice showed a markedly reduced susceptibility to DSSinduced colitis. While DSS treatment caused a marked increase in both CD4 + and CD8 + colonic T cells expressing increased levels of IL-2, IL-4, and IL-10 in wild type mice none of these changes were seen in IL-2 +/--mice. On the contrary, cytokine expression in intestinal T cells of IL-2 +/--mice was actually reduced after DSS treatment. These results suggest that reduced levels of IL-2 leads to attenuated activation and function of intestinal T cells in IL-2 +/--mice and a failure to react adequately to DSS exposure.

The staphylococcal enterotoxins (SEs) are the products of Staphylococcus aureus and are recognized as the causative agents of classical food poisoning in humans following the consumption of contaminated food. While illness evoked by ingestion of the SE or its producer organism in tainted food are often self-limited, our current understanding regarding the evolution of S. aureus provokes the utmost concern. The organism and its associated toxins, has been implicated in a wide variety of disease states including infections of the skin, heart, sinuses, inflammatory gastrointestinal disease, toxic shock, and Sudden Infant Death Syndrome. The intricate relationship between the various subsets of immunocompetent T cells and accessory cells and the ingested material found within the gastrointestinal tract present daunting challenges to the maintenance of immunologic homeostasis. Dysregulation of the intricate balances within this environment has the potential for extreme consequences within the host, some of which are long-lived. The focus of this review is to evaluate the relevance of staphylococcal enterotoxin in the context of mucosal immunity, and the underlying mechanisms that contribute to the pathogenesis of gastrointestinal autoimmune disease.