The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/7/217/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 1, July 1, 1998 217-222

Brief Definitive Reports

Reversal of Proinflammatory Responses by Ligating the Macrophage Fc{gamma} Receptor Type I

Fayyaz S. Sutterwala*, Gary J. Noel{ddagger}, Padmini Salgame*, and David M. Mosser*

From the * Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; and the {ddagger} Department of Pediatrics, Cornell University Medical College, New York 10021

Macrophages can respond to a variety of infectious and/or inflammatory stimuli by secreting an array of proinflammatory cytokines, the overproduction of which can result in shock or even death. In this report, we demonstrate that ligation of macrophage Fc{gamma} receptors (Fc{gamma}R) can lead to a reversal of macrophage proinflammatory responses by inducing an upregulation of interleukin (IL)-10, with a reciprocal inhibition of IL-12 production. IL-10 upregulation was specific to Fc{gamma}R ligation, since the ligation of the Mac-1 receptor did not alter IL-10 production. The identification of the specific Fc{gamma}R subtype responsible for IL-10 upregulation was determined in gene knockout mice. Macrophages from mice lacking the FcR {gamma} chain, which is required for assembly and signaling by Fc{gamma}RI and Fc{gamma}RIII, failed to upregulate IL-10 in response to immune complexes. However, mice lacking either the Fc{gamma}RII or the Fc{gamma}RIII were fully capable of upregulating IL-10 production, implicating Fc{gamma}RI in this process. The biological consequences of Fc{gamma}RI ligation were determined in both in vitro and in vivo models of inflammation and sepsis. In all of the models tested, the ligation of Fc{gamma}R promoted the production of IL-10 and inhibited the secretion of IL-12. This reciprocal alteration in the pattern of macrophage cytokine production illustrates a potentially important role for Fc{gamma}R-mediated clearance in suppressing macrophage proinflammatory responses.

Key Words: CD64 • macrophage • interleukin 10 • inflammation • Fc receptors

Address correspondence to David M. Mosser, Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad St., Philadelphia, PA 19140. Phone: 215-707-8262; Fax: 215-707-7788; E-mail: dmmosser{at}astro.ocis.temple.edu

F.S. Sutterwala was supported by the M.D./Ph.D. program at the Temple University School of Medicine. This work was supported by National Institutes of Health grant AI24313, and by a grant from the American Heart Association.


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