Regulation of neutrophil-derived chemokine expression by IL-10.
In this study, we examined IL-10 regulation of polymorphonuclear leukocyte (PMN)-derived chemokine expression. Studies demonstrated that IL-10 dose dependently suppressed the expression and production of PMN-derived macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-1 beta, IL-8 mRNA, and protein. Although inhibition of protein synthesis was found to superinduce the expression of PMN-derived chemokine steady-state mRNA, the inhibitory activity of IL-10 was completely abrogated in the presence of either cycloheximide or puromycin. These data suggest that the effect of IL-10 on PMN-derived chemokine expression was through the production of de novo repressor protein(s). Next, we examined the half-life (t1/2) of chemokine mRNA by LPS-treated PMNs in the presence or absence of IL-10. The t1/2 of MIP-1 alpha, MIP-1 beta, and IL-8 mRNA from PMNs treated for 4 h with LPS before actinomycin-D (Ac-D) addition were approximately 40 min, 1.7 h, and 2 h, respectively, whereas the t1/2 from PMNs stimulated for 8 h before Ac-D were 2, 2, and > 9 h, respectively. Interestingly, IL-10 significantly accelerated the decay of all three of the above chemokine mRNA. The t1/2 of MIP-1 alpha, MIP-1 beta, and IL-8 mRNA from PMNs treated with LPS plus IL-10 compared with LPS alone was reduced by 62, 50, and 40%, respectively, at the 4-h time point and by 50, 25, and 70%, respectively, at the 8-h time point. These findings support the notion that PMNs are an important cellular source of both C-X-C and C-C chemokines, and that IL-10 regulates both inflammatory/immune responses by not only modulating the activities of T cell, B cell, and mononuclear phagocyte function, but also by inhibiting PMN-derived chemokine expression.
Kasama
T
T
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
Strieter
R M
RM
Lukacs
N W
NW
Burdick
M D
MD
Kunkel
S L
SL
D001483:Base Sequence; D054407:Chemokine CCL4; D016207:Cytokines / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins; D008969:Molecular Sequence Data; D015846:Monokines / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics
D054407:Chemokine CCL4; D016207:Cytokines; D017931:DNA Primers; D016209:Interleukin-8; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016753:Interleukin-10