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

Throughout the body, immune cells of various types, both classical (such as T-cells) and less recognized (such as intestinal epithelial cells) are exp osed to a variety of neurotransmitters secreted from local nerve fibers. Mo reover, immune cells express specific neurotransmitter receptors. Based on the above we asked whether neurotransmitters, by direct interaction with th eir receptors, can either evoke or block immune functions in general, and c ytokine secretion in particular. We found that several neuropeptides (SOM, Sub P, CGRP and NPY), in nM conce ntration and in the absence of any additional stimulatory molecules, induce d a significant secretion of cytokines from Th0, Th1 and Th2 antigen specif ic T-cells. Moreover, some neuropeptides surprisingly drove committed Th1 and Th2 popul ations to a 'forbidden' cytokine secretion: secretion of Th2 cytokines from Th1 cells, and vice versa. We further found that SOM by itself markedly af fected the secretion of proinflammatory cytokines from intestinal epithelia l 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-alpha or bacteria (Salmon ella)-induced secretion of IL-8 and IL-1 beta from two intestinal epithelia l cell lines. Taken together, these observations suggest that neuropeptides can by themse lves induce both typical and atypical cytokine secretion from T-cells and i ntestinal epithelial cells. Since a myriad of immune reactivities are media ted by, and dependent on, specific cytokines secreted from immune cells, th e neuropeptide-induced effects may have important implications for numerous physiological and pathological conditions, including autoimmune diseases, chronic inflammation and neoplasias.