Regulation by transforming growth factor-beta 1 of expression and function of the receptor for IFN-gamma on mouse macrophages.
Transforming growth factor-beta (TGF-beta) is known phenomenologically as a negative regulator of several functions of mouse bone marrow macrophages. The studies reported here extend this list by showing that TGF-beta can suppress cytolytic activity of mouse bone marrow culture-derived macrophages that already have become activated by IFN-gamma and LPS for tumor cell killing, as well as confirm that this cytokine can interfere with the induction of activation. Suppression was caused by a shift in the dose response curve for IFN-gamma rather than absolute inhibition; the 50% effective dose for IFN-gamma was increased approximately fourfold by treatment with TGF-beta. TGF-beta also decreased the absolute number of IFN-gamma R on the surfaces of pretreated macrophages by approximately 30 to 35%, without altering the affinity with which IFN-gamma bound. The increased concentration of IFN-gamma needed to produce the higher level of receptor occupancy explained the observed shift in the IFN-gamma dose response curve. These results suggest that TGF-beta mediates its negative regulatory effects on macrophage activation by interfering with coupling of the IFN-gamma R to the pathways that induce and maintain macrophage activation for tumor cell killing. Such effects are consistent with the view that TGF-beta is a negative regulator of macrophage activation for tumor cell killing. Because of this fact, neoplastic cells that secrete this cytokine may have a distinct survival advantage.
Pinson
D M
DM
Wilkinson Laboratory of the Cancer Center, Department of Pathology and Oncology, University of Kansas Medical Center, Kansas City 66160-7184.
LeClaire
R D
RD
Lorsbach
R B
RB
Parmely
M J
MJ
Russell
S W
SW
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation; D007111:Immunity, Cellular / Q000187:drug effects; D007371:Interferon-gamma / Q000502:physiology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D011971:Receptors, Immunologic / Q000378:metabolism*; D017471:Receptors, Interferon; D016212:Transforming Growth Factor beta / Q000502:physiology*
D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma