IFN-gamma inhibits inflammatory cell recruitment and the evolution of bacterial cell wall-induced arthritis.
Localization of streptococcal cell wall Ag (SCW) in the synovial tissue of treated rats induces an influx of leukocytes and a cell-mediated immune response leading to arthritis and joint destruction. Systemic administration of the T cell product, IFN-gamma (10(6) U/kg/day), suppresses the recruitment of leukocytes into the synovium and effectively inhibits the inflammation and pathology characteristic of SCW-induced arthritis (articular index 10.4 +/- 0.6 for SCW vs 2.0 +/- 0.7 for SCW with IFN-gamma, p less than 0.005). Monocyte-macrophages from animals treated with IFN-gamma exhibited defective chemotactic responses when tested in vitro and furthermore, monocytes cultured with IFN-gamma (25 to 500 U/ml) in vitro had significantly suppressed chemotactic responses to the complement fragment C5a (p less than 0.005). The decreased ability to migrate to C5a was associated with decreased binding of fluorochrome-conjugated C5a indicative of reduced expression of C5a receptors. Based on these data, IFN-gamma that induces monocyte maturation as reflected by increased Ia expression conversely inhibits C5a receptor expression. Although locally elevated IFN-gamma levels may serve to inhibit recruitment away from an inflammatory site, systemic exposure to IFN-gamma appears to inhibit leukocyte recruitment to the inflammatory site by its ability to induce premature maturation and concomitant inability to respond to certain chemotactic ligands. Inasmuch as monocyte recruitment to the synovium is pivotal in the development of SCW-induced polyarthritis, the ability of IFN-gamma to inhibit this event effectively inhibits the synovial pathology.
Wahl
S M
SM
Cellular Immunology Section, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
Allen
J B
JB
Ohura
K
K
Chenoweth
D E
DE
Hand
A R
AR
D000818:Animals; D001168:Arthritis / Q000276:immunology*; D002473:Cell Wall / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D005260:Female; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism; D013297:Streptococcus pyogenes / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology
D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D007371:Interferon-gamma