CONTRIBUTION OF TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) IN HOST-DEFENSE MECHANISM AGAINST CRYPTOCOCCUS-NEOFORMANS

We investigated the role of TNF-alpha in the host defence mechanism ag ainst infection with a virulent strain of Cryptococcus neoformans. Adm inistration of exogenous recombinant human TNF-alpha significantly pro longed the survival time of mice infected by intratracheal instillatio n of the organism. Surprisingly, neutralizing MoAb to murine TNF-alpha did not shorten their survival time, a finding inconsistent with prev ious results. To investigate the cause of this inconsistency, we exami ned the production of TNF-alpha in the lungs of infected mice. During the course of cryptococcosis, there was little or no generation of TNF -alpha mRNA in the lung. This might be partly due to a direct inhibito ry action of the fungal microorganism on TNF-alpha production by macro phages. In vitro production of TNF-alpha by murine interferon-gamma (I FN-gamma)- and lipopolysaccharide (LPS)-stimulated macrophages was str ongly inhibited by co-culturing with the whole yeast cells. In contras t, administration of recombinant murine IL-12 markedly induced TNF-alp ha production and the neutralizing anti-TNF-alpha MoAb strongly blocke d IL-12-induced protection of mice against cryptococcal infection. The se results indicate that endogenously synthesized TNF-alpha has the po tential to contribute to the elimination of C. neoformans and partly m ediates the protective effect of IL-12.