Human macrophages acquire a hyporesponsive state of tumor necrosis factor alpha production in response to successive Mycobacterium avium serovar 4 stimulation

Abstract

Human macrophages (Mφ) from most donors respond to inoculation with Mycobacterium avium serovar 4 (M. avium) by tumor necrosis factor alpha (TNF- α) production, which is of critical importance for proper defense against microorganisms. An initial infection of Mφ with M. avium results in an incapacity to accumulate TNF-α 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 Mφ remain unresponsive to a subsequent M. avium stimulus to increase steady-state TNF-α mRNA, suggesting that prostaglandin E2 is instrumental for the adaptation to an M. avium challenge. TNF-α 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 Mφ response to M. avium is inhibited by staurosporin, an inhibitor of phospholipid Ca2+-dependent protein kinases, indicating that the initial and the successive TNF-α responses to M. avium are dependent on different mechanisms.