TGF-beta and IL-10 regulation of IFN-gamma produced in Th2-type schistosome granulomas requires IL-12

Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) regul ate CD4(+) T cell interferon-gamma (IFN-gamma) secretion in schistosome gra nulomas. The role of IL-12 was determined using C57BL/6 and CBA mice. C57BL /6 IL-4 -/- granuloma cells were stimulated to produce IFN-gamma when cultu red with IL-10 or TGF-beta neutralizing monoclonal antibody. In comparison, C57BL/6 wild-type (WT) control granuloma cells produced less IFN-gamma. IL -12, IL-18, and soluble egg antigen stimulated IFN-gamma release from C57BL /6 IL-4 -/- and WT mice. IFN-gamma production in C57 IL-4 -/- and WT granul omas was IL-12 dependent, because IL-12 blockade partly abrogated IFN-gamma secretion after stimulation. All granuloma cells released IL-12 (p70 and p 40), and IL-12 production remained constant after anti-TGF-beta, anti-IL-10 , recombinant IL-18, or antigen stimulation. C57 WT and IL-4 -/- mouse gran uloma cells expressed IL-12 receptor (IL-12R) beta1-subunit mRNA but little beta2 mRNA. TGF-beta or IL-10 blockade did not influence beta1 or b2 mRNA expression. CBA mouse dispersed granuloma cells released no measurable IFN- gamma, produced IL-12 p70 and little p40, and expressed IL-12R beta2 and li ttle beta1 mRNA. In T helper 2 (Th2) granulomas of C57BL/6 WT and IL-4 -/- mice, cells produce IL-12 (for IFN-gamma production) and IL-10 and TGF-beta modulate IFN-gamma secretion via mechanisms independent of IL-12 and IL-12 R mRNA regulation. We found substantial differences in control of granuloma IFN-gamma production and IL-12 circuitry in C57BL/6 and CBA mice.