Critical role of Toll-like receptors and the common TLR adaptor, MyD88, in induction of granulomas and liver injury

Pattern recognition receptors: A contemporary view on liver diseases

“…89 We found that priming with P. acnes or with TLR9 and TLR2 co-stimulation upregulates expression of TLR4 and MD-2 and set the stage for LPS-induced liver injury. 89,90 Consistent with this observation, in isolated Kupffer cells, TLR9 pre-stimulation resulted in sensitization to LPS-induced TNF␣ production suggesting that TLR9 ligands may sensitize the liver to subsequent stimulation via TLR4. 94 In contrast to TLR9, pretreatment with a TLR3 ligand attenuated LPS-induced liver injury by downregulation of TLR4 on macrophages.…”

“…171,172 An additional concern is that consecutive use of different TLR (TLR2, TLR4, TLR9) ligands may lead to immune paralysis, 173,174 or, as in case of combined TLR2 and TLR9 ligands, can result in sensitization to consecutive TLR4 stimulation and development of acute liver failure. 90 In the light of these recent discoveries, the involvement of pattern recognition receptors in therapy provides novel and promising grounds for amelioration of different liver diseases.…”

Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice

“…Alternatively, TLR4 with or without MD-2 may signal differently, or TLR4-MD-2 complex receptor may function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent signaling (13). We had previously reported a critical role of TLRs and the common TLR adaptor, MyD88, in other models of liver inflammation and injury (39); the exact signaling events downstream from TLR4-MD-2 complex in NASH are yet to be fully understood. Nevertheless, it is important to note that both TLR4 KO and MD-2 KO genotypes offered only partial protection against MCD diet-induced NASH, suggesting the possibility that TLR4/MD-2-independent events may be involved in the pathogenesis of NASH.…”

“…Serum alanine aminotransferase (ALT) was determined using a kinetic method [ALT Liquid, Advanced Diagnostics (South Plainfield, NJ) and D-TEK (Bensalem, PA)]; liver thiobarbituric acid reactive substances (TBARS) and triglycerides were measured as previously described, using commercial kits (39). Serum endotoxin was quantified using LAL assay (detection limit 0.1 EU/ml; Cambrex, Walkersville, MD).…”

“…Total RNA extraction from liver tissue and mRNA quantification using SYBR Green-based real-time quantitative polymerase chain reaction was performed as previously described (39). All specific mRNA levels were normalized against the housekeeping gene, 18S, in the same sample.…”