TUMOR-NECROSIS-FACTOR AS AN AUTOCRINE AND PARACRINE SIGNAL CONTROLLING THE MACROPHAGE SECRETORY RESPONSE TO CANDIDA-ALBICANS

We have previously demonstrated that the hyphal form of Candida albica ns (H-Candida), but not the yeast form (Y-Candida), acts as a macropha ge-stimulating agent. The early response (1 to 3 h) of the macrophage cell line ANA-1 to H-Candida results in enhanced tumor necrosis factor (TNF) transcription and production. Here we show that when coincubati on times are prolonged (3 to 24 h), Y-Candida also exhibits stimulator y properties. This phenomenon has been ascribed to the occurrence of t he dimorphic transition, as demonstrated by microscopic evaluation of the cultures and by experiments in which both killed Y-Candida and the agerminative strain C. albicans PCA-2 failed to induce cytokine produ ction. TNF produced in response to W-Candida acts as an autocrine and paracrine signal controlling the macrophage secretory response to C. a lbicans. In bet, addition of anti-TNF polyclonal antibodies to the coc ulture of ANA-I macrophages and H-Candida results in a marked and time -dependent decrease of TNF transcript levels. Moreover, pretreatment o f macrophages with recombinant TNF for 3 h enhances TNF and induces in terleukin-l production in response to both forms of Candida, while pre treatment for 18 h renders macrophages refractory to any stimuli. Inte restingly, the kinetics of interleukin-1 transcription and secretion i n response to H-Candida are delayed with respect to those of TNF. Over all, these data indicate that TNF, produced by macrophages in response to H-Candida, regulates its own production as well as that of other s oluble factors, thus suggesting that this cytokine plays multiple role s in the immune mechanisms involved in Candida infection.