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.
Beinborn
Martin
M
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.
Blum
Arthur
A
Hang
Long
L
Setiawan
Tommy
T
Schroeder
Jonathan C
JC
Stoyanoff
Korynn
K
Leung
John
J
Weinstock
Joel V
JV
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