TLRs, NF-κB, JNK, and Liver Regeneration

Abstract

While hepatocytes rarely undergo proliferation in normal livers, they quickly induce proliferation in response to loss of liver mass by toxin or inflammation-induced hepatocyte injury, trauma, or surgical resection, leading to a restoration of liver mass to its original size. Recent studies suggest that Toll-like receptor (TLR) signaling participates in this regenerative response. Myeloid differentiation factor (MyD88), a common adaptor molecule in the TLR, IL-1 and IL-18 receptor signaling, plays a key role, at least, in the early phase of liver regeneration. Currently, definite ligands which bind to TLRs and initiate this process are still unclear. TLRs stimulated by their corresponding ligands, as well as tumor necrosis factor (TNF) receptors (TNFRs), can activate downstream signal molecules, including transcription factor nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK). Previous studies have revealed the important role of TNF receptor signaling, NF-κB, and JNK in liver regeneration by using hepatocyte-specific gene-modified animals. This review will summarize the current knowledge of TLR signaling and their related molecules in liver regeneration. We will also discuss whether modulating these factors may become new therapeutic strategies to promote liver regeneration in various clinical situations.

Figure 1

Signal transduction pathways during the priming phase of liver regeneration. Interactions between Kupffer cells and hepatocytes are also illustrated while other nonparenchymal cells are also possibly involved. AP-1, activator protein; C3aR, activated compliment 3 receptor; C5aR, activated compliment 5 receptor; Gadd45β, growth arrest and DNA-damage-inducible gene 45β ; IKK, inhibitor of nuclear factor κB kinase; IL-6, interleukin-6; JAK, Janus-associated kinase; JNK, c-jun N-terminal kinase; MKK7, mitogen-activated protein kinase 7; MyD88, myeloid differentiation factor 88; NEMO, nuclear factor κB essential modulator; RIP, receptor interacting protein; TLR, toll-like receptor; TNFα, tumor necrosis factor α; TRIF, TIR-domain containing adaptor inducing interferon-β.