PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA IN HUMAN-LEUKOCYTES STIMULATED BY CRYPTOCOCCUS-NEOFORMANS

Tumor necrosis factor alpha (TNF-alpha) is a key mediator of inflammat ion and may promote human immunodeficiency virus replication in latent ly infected cells. Since cryptococcosis often is associated with aberr ations in the host inflammatory response and occurs preferentially in persons with AIDS, we defined the conditions under which human leukocy tes produce TNF-alpha when stimulated by Cryptococcus neoformans. Peri pheral blood mononuclear cells (PBMC) produced comparable amounts of T NF-alpha, following stimulation with C. neoformans and lipopolysacchar ide. Detectable TNF-alpha release in response to C. neoformans occurre d only when fungi,vith small-sized capsules were used and complement-s ufficient serum was added. Fractionation of PBMC established that mono cytes were the predominant source of TNF-alpha. TTF-alpha gene express ion and release occurred significantly later in PBMC stimulated with C . neoformans than in PBMC stimulated with LPS. C. neoformans was also a potent inducer of TNF-alpha from freshly isolated bronchoalveolar ma crophages (BAM). Upon in vitro culture, BAM and monocytes bound greate r numbers of fungal cells, yet their capacity to produce TNF-alpha fol lowing cryptococcal stimulation declined by 74 to 100%. However, this decline was reversed if the BAM and monocytes were cultured with gamma interferon. These data establish that C. neoformans can potently stim ulate TNF-alpha release from human leukocytes. However, several variab les profoundly affected the amount of TNF-alpha released, including th e type of leukocyte and its state of activation, the size of the crypt ococcal capsule, and the availability of opsonins.