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

Abstract

Interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) regulate CD4+ T cell interferon-γ (IFN-γ) secretion in schistosome granulomas. The role of IL-12 was determined using C57BL/6 and CBA mice. C57BL/6 IL-4 -/- granuloma cells were stimulated to produce IFN-γ when cultured with IL-10 or TGF-β neutralizing monoclonal antibody. In comparison, C57BL/6 wild-type (WT) control granuloma cells produced less IFN-γ. IL-12, IL-18, and soluble egg antigen stimulated IFN-γ release from C57BL/6 IL-4 -/- and WT mice. IFN-γ production in C57 IL-4 -/- and WT granulomas was IL-12 dependent, because IL-12 blockade partly abrogated IFN-γ secretion after stimulation. All granuloma cells released IL-12 (p70 and p40), and IL-12 production remained constant after anti-TGF-β, anti-IL-10, recombinant IL-18, or antigen stimulation. C57 WT and IL-4 -/- mouse granuloma cells expressed IL-12 receptor (IL-12R) β1-subunit mRNA but little β2 mRNA. TGF-β or IL-10 blockade did not influence β1 or β2 mRNA expression. CBA mouse dispersed granuloma cells released no measurable IFN-γ produced IL-12 p70 and little p40, and expressed IL-12R β2 and little β1 mRNA. In T helper 2 (Th2) granulomas of C57BL/6 WT and IL-4 -/mice, cells produce IL-12 (for IFN-γ production) and IL-10 and TGF-β modulate IFN-γ secretion via mechanisms independent of IL-12 and IL-12R mRNA regulation. We found substantial differences in control of granuloma IFN-γ production and IL-12 circuitry in C57BL/6 and CBA mice.