Human macrophages acquire a hyporesponsive state of tumor necrosis factor alpha production in response to successive Mycobacterium avium serovar 4 stimulation.
Human macrophages (M phi) from most donors respond to inoculation with Mycobacterium avium serovar 4 (M. avium) by tumor necrosis factor alpha (TNF-alpha) production, which is of critical importance for proper defense against microorganisms. An initial infection of M phi with M. avium results in an incapacity to accumulate TNF-alpha mRNA after reinfection with M. avium, indicating adaptation to a hyporesponsive state by preexposure of the cells to M. avium. Adaptation to stimulation with M. avium is abrogated by the cyclooxygenase inhibitor indomethacin. In the presence of prostaglandin E2, indomethacin-exposed, M. avium-treated M phi remain unresponsive to a subsequent M. avium stimulus to increase steady-state TNF-alpha mRNA, suggesting that prostaglandin E2 is instrumental for the adaptation to an M. avium challenge. TNF-alpha mRNA accumulation induced by a second M. avium stimulus in the presence of indomethacin is blocked by the protein tyrosine kinase inhibitor herbimycin. In contrast, the initial M phi response to M. avium is inhibited by staurosporin, an inhibitor of phospholipid Ca(2+)-dependent protein kinases, indicating that the initial and the successive TNF-alpha responses to M. avium are dependent on different mechanisms.
Gan
H
H
Department of Rheumatology and Immunology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Newman
G W
GW
Remold
H G
HG
D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D009162:Mycobacterium avium / Q000145:classification / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D012703:Serotyping; D012772:Shock, Septic / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone; D007213:Indomethacin