The effects of gamma-interferon on human peripheral blood monocyte/macrophage-mediated bone particle degradation.
gamma-Interferon (IFN-gamma) has recently been demonstrated to inhibit the ability of mononuclear phagocytes to degrade bone particles. We have further addressed the specificity, potency and mechanism of this activity using human recombinant IFN-gamma. Adherent peripheral blood mononuclear leukocytes from normal human volunteers were cultured with washed, sieved (less than or equal to 75 microns) 45Ca-labelled rat bone particles for 3 days, after which bone particle degradation (7.1 +/- 1.6%, n = 11) was calculated from the fraction of 45Ca released into the medium. As little as 5 U/ml IFN-gamma significantly suppressed bone particle degradation and 50 U/ml was associated with consistent marked suppression (74.0 +/- 3.5% inhibition, P less than 0.001, n = 11). IFN-gamma was not suppressive if added to cells 24 h or more after exposure to bone particles. Addition of indomethacin (10 microM) did not reverse the effect of IFN-gamma, suggesting that it was not prostaglandin-mediated. In addition, 1,25(OH)2D3 (10 nM) did not remove the inhibitory effect of IFN-gamma. Contact of mononuclear phagocytes with bone particles and secretion of soluble factors from these cells have both been demonstrated to play a role in their ability to degrade bone particles. IFN-gamma (50 U/ml) inhibited monocyte/macrophage interaction with another unopsonized surface, i.e., one micron fluorescent latex particles, decreasing the number of internalized particles from 12.6 +/- 2.9 per cell to 5.9 +/- 1.4 per cell (P less than 0.01, n = 15), as measured using flow cytometry. However, binding of bone particles by the cells was not diminished by IFN-gamma. Exogenous alpha-interferon and human recombinant IL-1 beta, TNF-alpha, and lymphotoxin did not alter bone particle degradation. In addition, endogenous IL-1 beta release from human monocyte/macrophages exposed to bone particles was negligible and unaffected by IFN-gamma. We conclude that IFN-gamma is a potent and specific inhibitor of monocyte/macrophage-mediated bone particle degradation, and that this activity does not appear to be due to effects on the ability of monocytes to bind bone particles or to release IL-1 in response to the particles.
Terkeltaub
R
R
Department of Medicine, San Diego VA Medical Center, University of California.
Firestein
G S
GS
Kornbluth
R S
RS
Martin
J
J
Curran
D
D
Manolagas
S
S
D000818:Animals; D001842:Bone and Bones; D002117:Calcitriol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007370:Interferon Type I; D007375:Interleukin-1; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002117:Calcitriol; D007213:Indomethacin