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© The Rockefeller University Press, 0022-1007/1997/6/1987/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 11, June 2, 1997 1987-1995

Article

Regulation of Interleukin-12 by Complement Receptor 3 Signaling

Thomas Marth and Brian L. Kelsall

From the Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Complement receptor type 3 (CR3, CD11b/CD18) serves as a receptor for a number of endogenous ligands and infectious organisms, and is involved in adhesion and host defense functions. Here, we report that signaling via CR3 plays an important role in regulating production of interleukin-12 (IL-12), a key mediator of cell-mediated immunity (CMI). We demonstrate with a variety of stimuli a dose-dependent, specific downregulation of IL-12 secretion by human monocytes in vitro after exposure to antibodies to CR3 (anti-CD11b and anti-CD18), as well as to the natural CR3 ligands, iC3b, and Histoplasma capsulatum. CR3 antibodies also suppressed interferon-{gamma} (IFN-{gamma}) production in cultures of human peripheral blood mononuclear cells (PBMC). We determined that one mechanism by which CR3 antibodies may suppress IL-12 production is by the inhibition of IFN-{gamma}–induced tyrosine phosphorylation. Finally, in a murine model of IL-12–dependent septic shock, we provide evidence that administration of CR3 antibodies leads to suppression of IL-12 and IFN-{gamma} in vivo. Our studies thus define a novel role for CR3 in regulating CMI functions via IL-12.

Address correspondence to Thomas Marth, Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 208921890. Phone: 301-496-9663; FAX: 301-402-2240. Dr. Marth's current address is Abteilung Innere Medizin II, Universitätskliniken des Saarlandes, 66421 Homburg/Saar, Germany. Phone: 49-6841-163222; FAX: 49-6841-163267; E-mail: intmar{at}med-rz.uni-sb.de

We would like to acknowledge Dr. Warren Strober for his helpful discussions and for reviewing the manuscript and thank Drs. Robert Seder, Sharon Wahl, Thomas Wynn, Alan Sher, John O'Shea, and Stephen Straus for helpful comments.

T. Marth is a recipient of a research grant by the Deutsche Forschungsgemeinschaft (Ma 1711/1-1 and 2-1).

1 Abbreviations used in this paper: CMI, cell-mediated immunity; DTH, delayed type hypersensitivity; ECL, enhanced chemiluminescence; HC, Histoplasma capsulatum; HRP, horseradish peroxidase; ICAM-1, intercellular adhesion molecule 1; LPG, lipophosphoglycan; SAC, Staphylococcus aureus cells; STAT1, signal transducers and activators of transcription 1.


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