Although recent clinical and experimental observations indicate the existence of mutual relationship between the nervous and immune system, the molecular mechanisms by which the two systems interact are just beginning to be studied. Neuropeptides that belong to the tachykinin family, such as substance P, neurokinin A and neurokinin B, could play an important immunoregulatory role in vivo based on the following observations: a) the presence of SP and NKA in the microenvironment of the lymphoid orgens; b) the existence of SP receptors on immune cells; and c) the in vitro immunomodulatory activity of SP and NKA. The major objective of this proposal is to determine whether SP and related tachykinins modulate the immune response through the regulation of cytokine expression. Preliminary results indicated that SP induced the production of IL-2 in murine T cells and T cells lines in a dose-dependent and specific manner, that SP induced the expression of IL-3 and GM-CSF, affecting the development of myeloid and erythroid colonies in vitro, and that the specific message for the NK-1R (high-affinity receptor for SP) can be identified in purified CD4+ T lymphocytes by RT-PCR. We propose to continue and expand the molecular analysis of the immunoregulatory effect of SP and related neurokinins by: a) determining whether SP and related neurokinins stimulate IL-4 and IFNgamma production, in addition to the established stimulatory effect on IL-2 production; b) investigating the molecular mechanisms, including transcriptional and posttranscriptional regulation, by which SP and NKA stimulate IL-2 production in normal splenocytes and T cell lines; and c) identifying and characterizing the NK-1R present on lymphocytes, in terms of sequence, cellular distribution, and functionality. The study of the molecular mechanisms by which neuropeptides regulate the expression of interleukins, and therefore affect the outcome of the immune response, will offer new insights in the immunomodulatory activity of the nervous system, and could lead to new ways of controlling and manipulating the immune system, especially in pathological conditions.