Effects of benzoxazinorifamycin KRM-1648 on cytokine production at sites of Mycobacterium avium complex infection induced in mice

Abstract

Although various antimicrobial agents exhibit appreciable microbicidal activity in the early phase (weeks 2 to 4) of Mycobacterium avium complex (MAC) infection induced in mice, progressive bacterial regrowth subsequently occurs. To clarify the reason for this pattern of changes, we studied changes in the levels of various cytokines in tissue at sites of infection (spleens and lungs) of MAC-infected mice which were or were not given a benzoxazinorifamycin, KRM-1648 (KRM). Levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) in tissues temporarily increased at around weeks 2 to 4 after infection, rapidly decreased thereafter, and returned to normal by week 8. Similar but somewhat delayed changes were noted for levels of interleukin 10 (IL-10) and transforming growth factor beta (TGF-β), immunosuppressive cytokines with macrophage (Mφ)-deactivating activity, in tissue, except that TGF-β levels in the spleen remained high during weeks 4 to 8. KRM treatment blocked the increase in the levels of all of those cytokines in tissue in the early phase of infection, most strongly at week 4. IL-6 levels were beneath the limit of detection throughout the observation period. Bacterial loads in the visceral organs decreased during the first 2 weeks, and KRM treatment markedly promoted this decrease. However, regrowth of MAC organisms began at weeks 2 to 4 and continued thereafter, even in KRM-treated mice. Splenocytes and splenic Mφs of MAC-infected mice (week 2) produced and/or released into the culture fluid significant amounts of TNF-α (in a cell-bound form), IFN-γ, and IL-10, but not TGF-β, during 3 days of cultivation. A substantial amount of TGF-β was produced during 2 weeks of cultivation of peritoneal Mφs. KRM itself did not significantly affect the IL-10- and TGF-β-producing ability of cultured Mφs. These findings suggest that IL-10 and TGF-β play important roles in the regrowth of MAC organisms seen during the course of KRM treatment.