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The Journal of Immunology, Vol 150, Issue 7 2892-2900, Copyright © 1993 by American Association of Immunologists

ARTICLES

TNF-alpha response of human monocyte-derived macrophages to Mycobacterium avium, serovar 4, is of brief duration and protein kinase C dependent

H Gan, G Newman, PL McCarthy and HG Remold
Department of Rheumatology and Immunology, Brigham's and Womens Hospital, Boston, MA.

Human monocyte-derived macrophages (M phi) from the majority of normal donors respond to inoculation with Mycobacterium avium, serotype 4, (MAI) by elaboration of the inflammatory monokines TNF-alpha, IL-1 beta, and IL-6, which are of central importance for the protection against bacterial and parasitic infections. Peak TNF-alpha mRNA levels were of brief duration, being maximal at 1.5 h, and were only slightly higher than background levels at 4 h. Increases of IL-1 beta and IL-6 mRNA levels, on the other hand, persisted for 48 to 72 h. In contrast to LPS, MAI induced the production of only small amounts of TNF-alpha protein in the first 12 h and of large amounts of IL-1 beta and IL-6 protein between 3 and 72 h. MAI-induced TNF-alpha transcripts, in contrast to LPS induced TNF-alpha transcripts, were highly unstable. Their accumulation was blocked and their t 1/2 significantly decreased by the protein kinase C inhibitor staurosporine. In contrast, LPS- induced increases of TNF-alpha mRNA levels and MAI-induced increases of IL-1 beta and IL-6 mRNA levels were PKC independent. The cAMP- and cGMP- dependent protein kinase inhibitors, KT5720 and KT5823, respectively, and the tyrosine kinase inhibitors herbimycin and erbstatin had no effect on the MAI-dependent mRNA accumulation of TNF-alpha, IL-1 beta, and IL-6. W7, a calmodulin-dependent protein kinase inhibitor, was inhibitory in all cases. Thus, MAI-induced TNF-alpha mRNA accumulation is of short duration and PKC dependent. MAI-induced TNF-alpha protein production is low, possibly resulting in a mitigated antimicrobial effect.


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