TGF-beta 1 suppresses [correction of supresses] myeloid Fc gamma receptor function by regulating the expression and function of the common gamma-subunit.
We have previously reported that FcgammaR-mediated function in myeloid cells is a tightly regulated event that is influenced by the cytokines present in the milieu. TGF-beta1 is an immunosuppressive cytokine with pleiotropic effects on immune responses; however, the molecular mechanism by which TGF-beta suppresses immune responses is poorly understood. In this study, we have analyzed the effect of TGF-beta on FcgammaR-mediated activation of myeloid cells. We report that TGF-beta1-treated THP-1 human myeloid cells displayed reduced ability to phagocytose IgG-coated particles. Because FcgammaR expression is modulated by cytokines, we analyzed expression levels of FcgammaRI, FcgammaRIIa, FcgammaRIIb, and FcgammaRIIIa in cells cultured with or without TGF-beta1 and found while total protein levels of the FcgammaR were not reduced, surface expression of FcgammaRI and FcgammaRIII was lower in cells cultured with TGF-beta1. Concomitantly, there was a dose-dependent reduction in the expression of the FcgammaR-associated gamma-subunit. This suppressive effect of TGF-beta was likewise observed in bone marrow-derived murine myeloid cells and human monocytes. Importantly, TGF-beta1 also significantly reduced the production of monocyte chemoattractant protein-1 induced by immobilized IgG, which would further reduce monocyte recruitment to the site of inflammation. In contrast, human alveolar macrophages were refractory to this effect, expressing low levels of TGF-beta type II receptors compared with peripheral blood monocytes from the same donor. These data provide insight into the regulation of immune responses by TGF-beta1 and demonstrate the selectivity of these effects.
Tridandapani
Susheela
S
Department of Internal Medicine and Dorothy M. Davis Heart and Lung Research Institute, and The James Cancer Hospital and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA. tridandapani.2@osu.edu
Wardrop
Richard
R
Baran
Christopher P
CP
Wang
Yijie
Y
Opalek
Judy M
JM
Caligiuri
Michael A
MA
Marsh
Clay B
CB
D000818:Animals; D002461:Cell Line, Transformed; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D010587:Phagocytosis / Q000276:immunology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D018932:Chemokine CCL2; C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D021122:Protein Subunits; D017452:Receptors, IgG; D020395:Receptors, Interleukin-7; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1