Presence of Lps(d) mutation influences cytokine regulation in vivo by the Mycoplasma arthritidis mitogen superantigen and lethal toxicity in mice infected with M-arthritidis

The Mycoplasma arthritidis mitogen (MAM) superantigen (SAg) is a potent act ivator of human and murine cells and is produced by an organism that is a c ause of acute and chronic arthritis of rodents, It is phylogenetically unre lated to other bacterial SAgs and exhibits a number of unique features, We recently demonstrated that MAM differentially regulates the cytokine respon ses of different mouse strains following in vivo administration. Here we sh ow that the presence in inbred C3H/HeJ mice of the mutant Lps(d) gene, whic h is associated with a defect in Toll-like receptor 4 (TLR4), influences MA M regulation of cytokine profiles in vivo. Whereas the levels of type 1 cyt okines (interleukin-2 [IL-2], gamma interferon, IL-12, and tumor necrosis f actor alpha) were depressed in cells from MAM-injected wild-type C3H/HeSnJ mice, they were elevated in cells from C3H/HeJ mice. Furthermore, the level s of type 2 cytokines (IL-4, IL-6, and IL-10) were elevated in Lps(n) C3H/H eSnJ mice but depressed in Lpsd C3H/HeJ mice, The transcript for IL-12 p40 was highly expressed in C3H/HeJ but not C3H/HeSnJ mice, F, mice exhibited t he same cytokine profile as C3H/HeJ mice, indicating that the mutant gene e xhibited dominant-negative inheritance. In addition, C3H/HeJ mice were high ly susceptible to toxic death in comparison with C3H/HeSnJ mice after injec tion with live M. arthritidis organisms. Our results suggest that MAM inter acts with the lipopolysaccharide signaling pathway, possibly involving TLR4 or a combinatorial Toll complex.