Gan H, Newman G W, Remold H G
Department of Rheumatology and Immunology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Infect Immun. 1995 May;63(5):1921-6. doi: 10.1128/iai.63.5.1921-1926.1995.
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.
大多数供体的人类巨噬细胞（M phi）接种鸟分枝杆菌血清型4（M. avium）后会产生肿瘤坏死因子α（TNF-α），这对于有效抵御微生物至关重要。M phi初次感染M. avium后，再次感染M. avium时就无法积累TNF-α mRNA，这表明细胞预先接触M. avium后会适应低反应状态。环氧化酶抑制剂吲哚美辛可消除对M. avium刺激的适应性。在前列腺素E2存在的情况下，经吲哚美辛处理、M. avium处理的M phi对随后的M. avium刺激仍无反应，无法增加稳态TNF-α mRNA，这表明前列腺素E2有助于适应M. avium的挑战。在吲哚美辛存在的情况下，第二次M. avium刺激诱导的TNF-α mRNA积累被蛋白酪氨酸激酶抑制剂赫曲霉素阻断。相反，M phi对M. avium的初始反应被磷脂钙（2+）依赖性蛋白激酶抑制剂星形孢菌素抑制，这表明对M. avium的初始和后续TNF-α反应依赖于不同的机制。
