Macrophage control of mycobacterial growth induced by picolinic acid is dependent on host cell apoptosis

The effects of picolinic acid (PA) on the intramacrophagic growth of Mycoba cterium avium were studied. PA reduced M. avium growth inside mouse macroph ages and led to a complete control of mycobacterial growth when added toget her with IFN-gamma. The mechanism involved did not require TNF-alpha, NO, o r the respiratory burst, and was not dependent on either iron or,zinc withh olding, The mycobacteriostatic activity of the macrophages was associated w ith the induction of morphological changes that culminated in apoptosis at day 4 of treatment. PA alone induced apoptosis in macrophages, and this eff ect was increased by IFN-gamma treatment. Apoptosis at day 4 of infection w as reduced by inhibiting macrophage activation with the prostaglandin 15 de oxyprostaglandin J(2) or by treating the cells with the antioxidant N-acety lcysteine. Mycobacterial growth was partially restored in macrophages treat ed with PA and IFN-gamma when 15 deoxy-prostaglandin J(2) was added, concom itant with a delay in apoptosis, N-Acetylcysteine or glutathione could also completely revert the mycobacteriostatic effects of PA or PA plus IFN-gamm a.