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IL-12 Induction of mRNA Encoding Substance P in Murine Macrophages from the Spleen and Sites of Inflammation¹

Razvan Arsenescu^2,*, Arthur M. Blum, Ahmed Metwali, David E. Elliott and Joel V. Weinstock

^* Department of Internal Medicine, University of Kentucky, Lexington, KY 40515; and Department of Internal Medicine, University of Iowa, Iowa City, IA 52242

Substance P (SP), a neuropeptide, interacts with the neurokinin 1 receptor (NK-1R) on immune cells to help control IFN- production. In murine schistosomiasis mansoni, schistosome worms produce ova that incite focal Th2-type granulomatous inflammation within the liver and intestines. Normal gut is characterized by a controlled state of inflammation. IL-10 knockout mice develop chronic Th1-type colitis spontaneously. Both schistosome granulomas and gut mucosa display an SP immune regulatory circuit. However, the origin and regulation of SP production at these sites of inflammation are poorly understood. Macrophages are a potential source of SP. We therefore studied macrophages (F4/80⁺) from these models of inflammation. SP mRNA (preprotachykinin A (PPT A)) was detected within the schistosome granuloma, spleen, and lamina propria macrophages. Compared with those from wild-type mice, granuloma macrophages from STAT6^–/– mice had 10-fold higher PPT A mRNA expression, whereas in STAT4^–/– animals, PPT A mRNA expression was nearly abolished. IL-12 signals via STAT4 to induce Th1-type inflammation. It was demonstrated that IL-12, but not IL-18, induces SP mRNA expression in resting splenic macrophages from Schistosoma-infected mice and in wild-type lamina propria mononuclear cells. Thus, macrophages are a source for SP at these sites of chronic inflammation, and IL-12 and STAT4 are regulators of macrophage SP mRNA expression.

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				H. W. KOON and C. POTHOULAKIS Immunomodulatory Properties of Substance P: The Gastrointestinal System as a Model Ann. N.Y. Acad. Sci., November 1, 2006; 1088(1): 23 - 40. [Abstract] [Full Text] [PDF]