LPS-induced TNF-α factor (LITAF)-deficient mice express reduced LPS-induced cytokine: Evidence for LITAF-dependent LPS signaling pathways

Previously we identified a transcription factor, LPS-Induced TNF-α Factor (LITAF), mediating inflammatory cytokine expression in LPS-induced processes. To characterize the role of LITAF in vivo , we generated a macrophage-specific LITAF-deficient mouse (macLITAF −/− ). Our data demonstrate that in macrophages ( i ) several cytokines (such as TNF-α, IL-6, sTNF-RII, and CXCL16) are induced at lower levels in macLITAF −/− compared with LITAF +/+ control macrophages; ( ii ) macLITAF −/− mice are more resistant to LPS-induced lethality. To further identify LITAF signaling pathways, we tested mouse TLR-2 −/− , -4 −/− , and -9 −/− and WT peritoneal macrophages exposed to LPS. Using these cells, we now show that LITAF expression can be induced after challenge either with LPS from Porphyromonas gingivalis via agonism at TLR-2, or with LPS from Escherichia coli via agonism at TLR-4, both requiring functional MyD88. We also show that, in response to LPS, the MyD88-dependent LITAF pathway differs from the NF-κB pathway. Furthermore, using a kinase array, p38α was found to mediate LITAF phosphorylation and the inhibition of p38α with a p38-specific inhibitor (SB203580) blocked LITAF nuclear translocation and reduced LPS-induced TNF-α protein levels. Finally, macLITAF −/− macrophages rescued by LITAF cDNA transfection restored levels of TNF-α similar to those observed in WT cells. We conclude that LITAF is an important mediator of the LPS-induced inflammatory response that can be distinguished from NF-κB pathway and that p38α is the specific kinase involved in the pathway linking LPS/MyD88/LITAF to TNF.