Nerve-driven immunity: Neuropeptides regulate cytokine secretion of T cells and intestinal epithelial cells in a direct, powerful and contextual manner

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Abstract
Throughout the body, immune cells of various types, both classical (such as T-cells) and less recognized (such as intestinal epithelial cells) are exposed to a variety of neurotransmitters secreted from local nerve fibers. Moreover, immune cells express specific neurotransmitter receptors. Based on the above we asked whether neurotransmitters, by direct interaction with their receptors, can either evoke or block immune functions in general, and cytokine secretion in particular. We found that several neuropeptides (SOM, Sub P, CGRP and NPY), in nM concentration and in the absence of any additional stimulatory molecules, induced a significant secretion of cytokines from Th0, Th1 and Th2 antigen specific T-cells. Moreover, some neuropeptides surprisingly drove committed Th1 and Th2 populations to a ‘forbidden’ cytokine secretion: secretion of Th2 cytokines from Th1 cells, and vice versa. We further found that SOM by itself markedly affected the secretion of proinflammatory cytokines from intestinal epithelial cells, which play a major role in the gut immunity in the mucosal defense against invading microorganisms. Thus, somatostatin, through its specific receptor, inhibits (>90%) of the spontaneous, TNF-α or bacteria (Salmonella)-induced secretion of IL-8 and IL-1β from two intestinal epithelial cell lines. Taken together, these observations suggest that neuropeptides can by themselves induce both typical and atypical cytokine secretion from T-cells and intestinal epithelial cells. Since a myriad of immune reactivities are mediated by, and dependent on, specific cytokines secreted from immune cells, the neuropeptide-induced effects may have important implications for numerous physiological and pathological conditions, including autoimmune diseases, chronic inflammation and neoplasias.