Contribution of tumour necrosis factor‐alpha (TNF‐α) in host defence mechanism against Cryptococcus neoformans

We investigated the role of TNF‐α in the host defence mechanism against infection with a virulent strain of Cryptococcus neoformans. Administration of exogenous recombinant human TNF‐α significantly prolonged the survival time of mice infected by intratracheal instillation of the organism. Surprisingly, neutralizing MoAb to murine TNF‐α did not shorten their survival time, a finding inconsistent with previous results. To investigate the cause of this inconsistency, we examined the production of TNF‐α in the lungs of infected mice. During the course of cryptococcosis, there was little or no generation of TNF‐α mRNA in the lung. This might be partly due to a direct inhibitory action of the fungal microorganism on TNF‐α production by macrophages. In vitro production of TNF‐α by murine interferon‐gamma (IFN‐γ)‐ and lipopolysaccharide (LPS)‐stimulated macrophages was strongly inhibited by co‐culturing with the whole yeast cells. In contrast, administration of recombinant murine IL‐12 markedly induced TNF‐α production and the neutralizing anti‐TNF‐α MoAb strongly blocked IL‐12‐induced protection of mice against cryptococcal infection. These results indicate that endogenously synthesized TNF‐α has the potential to contribute to the elimination of C. neoformans and partly mediates the protective effect of IL‐12.