Inherited IL-12 unresponsiveness contributes to the high LPS resistance ofthe Lps(d) C57BL/10ScCr mouse

Lps(d) mouse strains are characterized by the presence of a defective Lps/t lr4 gene that make them refractory to the biological activity of LPS, One o f the mouse strains commonly used to study LPS defects is the C57BL/10ScCr (Cr) strain. However, unlike other Lpsd strains, the Cr strain also has a h eavily impaired IFN-gamma response to micro-organisms. As a consequence, un like other Lpsd mouse strains, they do not acquire a partial LPS susceptibi lity when treated with sensitizing bacteria. Because IL-12 is important for the microbial induction of IFN-gamma, we investigated whether the producti on or function of IL-12 might be defective in Cr mice, IL-12 mRNA (p35 and p40) was present in the spleen of untreated Cr mice, IL-12p40 mRNA was indu cible in mice injected with live or killed Salmonella typhimurium, and IL-1 2 (p70) was inducible in macrophages by bacteria. Thus, Cr mice exhibit nor mal IL-12 responses. In functional tests, splenocytes of untreated or of S. typhimurium-infected mice failed to produce IFN-gamma when stimulated with murine rIL-12 or with a combination of IL-12 and murine rIL-18 or Con A. F urthermore, Cr mice were identical with IL-12p35/p40 and IL-12 receptor bet a (1) knockout mice in their impaired in vivo and in vitro IFN-gamma respon ses to bacteria. Thus, Cr mire tarry a second genetic defect unrelated to t he Lps/tlr4 mutation that underlies the IL-12 unresponsiveness and contribu tes to the LPS resistance and impaired innate immune response in this strai n.