Interaction of Mycobacterium tuberculosis-induced transforming growth factor beta 1 and interleukin-10

Mycobacterium tuberculosis is associated with the activation of cytokine ci rcuits both at sites of active tuberculosis in vivo and in cultures of mono nuclear cells stimulated by M. tuberculosis or its components in vitro. Int eractive stimulatory and/or inhibitory pathways are established between cyt okines, which may result in potentiation or attenuation of the effects of e ach molecule on T-cell responses. Here we examined the interaction of trans forming growth factor beta 1 (TGF-beta 1) and interleukin-10 (IL-10) in pur ified protein derivative (PPD)-stimulated human mononuclear cell cultures i n vitro. TGF-beta 1 induced monocyte IL-10 (but not tumor necrosis factor a lpha) production (by 70-fold, P < 0.02) and mRNA expression in the absence but not in the presence of PPD. Both exogenous recombinant (r) IL-10 and rT GF-beta 1 independently suppressed the production of PPD-induced gamma inte rferon (IFN-gamma) in mononuclear cells from PPD skin test-positive individ uals. Synergistic suppression of IFN-gamma in cultures containing both rTGF -beta 1 and rIL-10 was only seen when the responder cell population were pe ripheral blood mononuclear cells (PBMC) and not monocyte-depleted mononucle ar cells and when PBMC were retreated with rTGF-beta 1. but not with rIL-10 . Suppression of PPD-induced IFN-gamma in PBMC containing both rTGF-beta 1 (1 ng/ml) and rIL-10 (100 pg/ml) was 1.5-fold higher (P < 0.05) than cultur es containing TGF-beta 1 alone and 5.7-fold higher (P < 0.004) than culture s containing IL-10 alone. Also, neutralization of endogenous TGF-beta 1 and IL-10 together enhanced PPD-induced IFN-gamma in PBMC in a synergistic man ner. Thus, TGF-beta 1 and IL-10 together potentiate the downmodulatory effe ct on M. tuberculosis-induced T-cell production of IFN-gamma, and TGF-beta 1 alone enhances IL-10 production. At sites of active M. tuberculosis infec tion, these interactions may be conducive to the suppression of mononuclear cell functions.