Transforming growth factor‐β inhibits interleukin‐12‐induced production of interferon‐γ by natural killer cells: A role for transforming growth factor‐β in the regulation of T cell‐independent resistance to Toxoplasma gondii

Abstract

Severe-combined immune deficient (SCID) mice have been found to resist infection with the intracellular protozoan parasite Toxoplasma gondii via interleukin (IL)-12 stimulation of interferon (IFN)-gamma production by natural killer (NK) cells. Previously, we demonstrated the presence of increased levels of transcripts for transforming growth factor-beta (TGF-beta) in the brains and lungs of SCID mice infected with T. gondii, leading us to investigate the role of TGF-beta in the mechanism of resistance to T. gondii in these mice. Stimulation of splenocytes from SCID mice with heat-killed T. gondii resulted in production of low levels of IFN-gamma and a two to threefold increase in levels of TGF-beta in the culture supernatants. Production of IFN-gamma in these cultures was increased three to fourfold by addition of anti-TGF-beta antibody. Stimulation of splenocytes from SCID mice with IL-12 in combination with either TNF-alpha or IL-1 beta resulted in production of high levels of IFN-gamma. Addition of TGF-beta to these cultures inhibited production of IFN-gamma in a dose-dependent manner. Immunohistochemical studies revealed increased levels of TGF-beta protein in the spleens of SCID mice 5 days after oral infection with the ME49 strain of T gondii, and brains of SCID mice at 18 days post-infection. However, no difference was detected in the levels of TGF-beta transcripts in the spleens of uninfected mice or mice infected for 5 days. To test whether TGF-beta could antagonize IL-12 mediated resistance to T. gondii in vivo, we administered TGF-beta to SCID mice infected with T. gondii. This treatment resulted in earlier mortality of infected mice and significantly reduced the ability of exogenous IL-12 to delay time-to-death. Administration of anti-TGF-beta to SCID mice, beginning 24 h prior to infection and every 2 days thereafter, delayed significantly time-to-death. Together, our data demonstrate that TGF-beta antagonizes the ability of IL-12 to stimulate production of IFN-gamma by splenocytes from SCID mice, and suggest a role for TGF-beta in regulation of T cell-independent resistance to T. gondii.

Interferon-α/β inhibition of interleukin 12 and interferon-γ productionin vitroand endogenously during viral infection

“…Other known inhibitors are transforming growth factor ␤ (TGF-␤) and IL-10. Unlike IFN-␣͞␤, TGF-␤ has been reported to inhibit the effect of IL-12 without appreciably altering the levels of factor production (16,(25)(26)(27). On the other hand, IL-10 is reported to inhibit NK cell IFN-␥ production indirectly through its inhibition of IL-12 expression (27,28).…”

Functional Analysis of Cathepsin B-like Cysteine Proteases fromLeishmania donovani Complex

“…Also, susceptibility to Leishmania chagasi infection in BALB/c mice is correlated with the localized production of TGF-␤1 at the site of maximal parasite growth in the liver (8). Application of anti-TGF-␤ antibodies arrested the development of lesions in mice, whereas treatment with TGF-␤ exacerbated the infection with L. amazonensis, Trypanosoma cruzi, and Toxoplasma gondii (9). L. major, Leishmania mexicana, and Leishmania braziliensis trigger the production of TGF-␤ and IL-10, which inhibit killing of intracellular organisms (10).…”

The role of IL-12 in experimental Trypanosoma cruzi infection

“…IL-10 and TGF-ß have also been shown to strongly influence the synthesis and/or effects mediated by IL-12 and are important regulators of IL-12-induced IFN-γ synthesis by NK cells (18,19). Whereas IL-10 appears to be a potent inhibitor of IL-12 synthesis by macrophages exposed to microbial products, the mechanism by which TGF-ß inhibits IFN-γ synthesis by NK cells is unknown.…”