TRANSFORMING GROWTH-FACTOR-BETA IN HUMAN CUTANEOUS LEISHMANIASIS

Transforming growth factor (TGF)-beta has several downregulatory funct ions on the immune system: inhibition of interleukin-2 receptor induct ion, decrease of interferon-gamma-induced class II antigen expression, inhibition of macrophage activation, as well as cytotoxic and lymphok ine-activated killer cell generation. TGF-beta has also been recognize d as an important immunoregulator in murine leishmaniasis, for which i t increases susceptibility to disease. In the present stud we evaluate the involvement of TGF-beta in human leishmaniasis in vitro and in pa tients with cutaneous leishmaniasis. Human macrophages produce active TGF-beta after infection by Leishmania amazonensis (480 +/- 44.7 pg/ml ; mean +/- SEM), L. donovani chagasi (295 +/- 7.6 pg/ml), or L. brazil iensis (196 +/- 15.7 pg/ml). When TGF-beta was added to cultures of hu man macrophages infected with L. braziliensis it led to an increase of approximately 50% in parasite numbers as compared with untreated cult ures. Exogenous TGF-beta added to macrophage cultures was able to reve rse the effect of interferon-gamma in controlling Leishmania growth. E ven at 100 IU/ml interferon-gamma the presence of TGF-beta increases t he number of intracellular parasites. On the other hand, TNF-alpha at high concentration (100 IU/ml) totally blunts the suppressive effect o f TGF-beta. Immunostaining for TGF-beta was observed in the dermis, pr oduced by fibroblasts and occasionally by inflammatory cells in the bi opsies from human leishmaniasis lesions, being present in most of the biopsies taken from patients with early cutaneous leishmaniasis (less than 2 months of ulcer development) and in cases of active mucosal lei shmaniasis. Taken together these observations suggest an important rol e for TGF-beta in human leishmaniasis, with its production by infected macrophages being probably related to parasite establishment in the e arly states of the disease.