Cytokine modulation of Mycobacterium lepraemurium infection in mice; important involvement of tumor necrosis factor, interleukin-2 and dissociation from macrophage activation

Abstract

Susceptible BALB/c and resistant A/J mice were infected by the intravenous route with 10(7) Mycobacterium lepraemurium (MLM), and mortality was followed in controls and in experimental animals infused i.p. with interleukin-2 (IL-2), tumour necrosis factor alpha (TNF alpha) and interferon-gamma (IFN gamma). BALB/c mice injected with buffer and 10(7) M. lepraemurium i.v. died significantly earlier than A/J mice (111 days vs 158 days, respectively P less than 0.001), confirming earlier reports. Infusion of IFN gamma (1 or 2 micrograms every day) led to no significant increase in survival of both strains of mice infected with M. lepraemurium. Injection of IL-2 (1 microgram/day) led to a moderate increase in survival time in both strains of mice (P less than 0.01) although not changing the differences between resistant and susceptible strains of mice. Injection of tumour necrosis factor (1 microgram/day) significantly enhanced survival time in both strains (P less than 0.001), although all infected mice eventually died. The beneficial effect of IL-2 and TNF alpha on progression of the disease was seen as a modest reduction in bacterial growth in the lymph nodes and livers of BALB/c mice injected subcutaneously (approximately a one-log reduction in bacterial numbers). There was no evidence that the beneficial effect seen in vivo in mice was related to superior macrophage activation, inasmuch as peritoneal macrophages from untreated infected mice released similar amounts of superoxide anion, upon PMA triggering, as macrophages from infected and cytokine-treated mice. Moreover, macrophages from infected mice responded better to IFN gamma than cells from uninfected mice, in terms of developing tumour cytotoxicity in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)