Regulation of activated macrophage antimicrobial activities. Cooperation of lymphokines for induction of resistance to infection

Macrophages treated with the soluble products of Ag-stimulated spleen cells from bacillus Calmette-Guérin-infected C3H/HeN mice (lymphokines) (LK] before infection developed the capacity to resist infection with obligately intracellular amastigotes of the protozoan parasite, Leishmania major: 40 to 60% fewer cells in LK-treated cultures were infected 2 h after exposure to parasites than cells in medium-treated controls. Macrophages treated with LK depleted of IFN-gamma failed to acquire this activated macrophage effector activity. Paradoxically, IFN-gamma by itself was also not effective. Activity of the ineffective, IFN-gamma-depleted LK was restored, however, by addition of 10 to 100 U/ml IFN-gamma, itself inactive. The induction of this antimicrobial activity was the result of the interaction of macrophages and several molecularly distinct LK, and IFN-gamma was a necessary but insufficient activation signal. The activation of macrophage resistance to infection by LK was 1) not signal sequence dependent, 2) absent in cells treated with the second signal at lower (4 degrees C) temperatures and in the presence of protein synthesis inhibitors, and 3) induced by the cooperation of IFN-gamma and LK of m.w. 45,000 and 33,000. These factors in LK constituted more than 85% total LK activity for induction of resistance to infection. A minor activity in LK, of m.w. 20,000, could apparently induce this effector activity in the absence of IFN-gamma: this activity was less than 15% of total LK activity.