TGF-beta regulates T-cell neurokinin-1 receptor internalization and function.
Substance P (SP) is a proinflammatory mediator implicated in inflammatory bowel disease (IBD) and other inflammatory states. SP acts by stimulating the neurokinin-1 receptor (NK-1R) on T lymphocytes and other cell types, and regulates these cells in a complex interplay with multiple cytokines. The mechanisms of interaction among these inflammatory mediators are not yet fully understood. Here, we demonstrate that function of the NK-1R, a member of the G protein-coupled receptor (GPCR) superfamily, is modulated by TGF-beta. The latter acts not on a GPCR but via serine-threonine kinase-class receptors. By flow confocal image analysis, we demonstrate that TGF-beta delays SP-induced NK-1R internalization on mucosal T cells isolated from a mouse model of IBD and on granuloma T cells in murine schistosomiasis. Furthermore, luciferase reporter-gene assays revealed that NK-1R stimulation activates the nuclear factor of activated T cell- and activator protein-1-dependent signaling pathways, which are known triggers of effector T-cell cytokine production. TGF-beta markedly increases SP-induced activation of these signaling cascades, suggesting that delayed NK-1R internalization results in enhanced signaling. Providing a link to amplified immune function, SP and TGF-beta, when applied in combination, trigger a strong release of the proinflammatory cytokines IFN-gamma and IL17 from intestinal inflammatory T cells, whereas either agonist alone shows no effect. These observations establish precedent that members of two distinct receptor superfamilies can interact via a previously unrecognized mechanism, and reveal a paradigm of GPCR transregulation that is relevant to IBD and possibly other disease processes.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, and Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Martin
M
Beinborn
Arthur
A
Blum
Long
L
Hang
Tommy
T
Setiawan
Jonathan C
JC
Schroeder
Korynn
K
Stoyanoff
John
J
Leung
Joel V
JV
Weinstock
D000818:Animals; D002460:Cell Line; D004705:Endocytosis; D005434:Flow Cytometry; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D018040:Receptors, Neurokinin-1 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D018040:Receptors, Neurokinin-1; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D013373:Substance P