Neuroendocrine-induced synthesis of bone marrow-derived cytokines with inflammatory immunomodulating properties

Although cytokines and other soluble regulators of immunity are known to be involved in hematopoiesis, Little is known about the signals that induce t he synthesis of those mediators locally. Based on recent studies linking th e neuroendocrine hormone thyrotropin [thyroid-stimulating hormone (TSH)] to immune cell function in other tissues, we investigated the capacity of TSH to activate cytokine responses from bone marrow cells, These studies revea l that stimulation of the TSH receptor on bone marrow cells-using highly pu rified or recombinant TSH or by direct stimulation with anti-TSH receptor a ntibodies-rapidly induces the synthesis of cytokines from bone marrow cells that are classically used in the regulation of inflammatory responses. Of 13 cytokines screened for activity by ELISA or by RNase protection assays f or gene expression, IL-6, IFN-beta, TNF alpha, TNF beta, TGF beta 2, and ly mphotoxin-beta responses were reproducibly induced by TSH within 2-3 h of s timulation. Intracellularly, TSH stimulation of bone marrow cells caused ra pid increases in cAMP levels and induced the phosphorylation of the Jak2 pr otein kinase, thereby defining a novel G-protein coupled receptor/cytokine synthesis pathway. These findings demonstrate that TSH can serve as a prima ry inductive signal of cytokine production by bone marrow cells. (C) 1999 A cademic Press.