Lipopolysaccharide stimulates the MyD88-independent pathway and results inactivation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes

Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4, a member of the TLR family that participates i n pathogen recognition. TLRs recruit a cytoplasmic protein, MyD88, upon pat hogen recognition, mediating its function for immune responses. Two major p athways for LPS have been suggested in recent studies, which are referred t o as MyD88-dependent and -independent pathways. We report in this study the characterization of the MyD88-independent pathway via TLR4. MyD88-deficien t cells failed to produce inflammatory cytokines in response to LPS, wherea s they responded to LPS by activating IFN-regulatory factor 3 as well as in ducing the genes containing IFN-stimulated regulatory elements such as IP-1 0. In contrast, a lipopeptide that activates TLR2 had no ability to activat e IFN-regulatory factor 3. The MyD88-independent pathway was also activated in cells lacking both MyD88 and TNFR-associated factor 6. Thus, TLR4 signa ling is composed of at least two distinct pathways, a MyD88-dependent pathw ay that is critical to the induction of inflammatory cytokines and a MyD88/ TNFR-associated factor 6-independent pathway that regulates induction of IP -10.