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Tumor Necrosis Factor Member Promotes Sustained Toll-Like Receptor Signaling

Macrophages of the innate immune system have Toll-like receptors (TLRs) that recognize bacterial components such as lipopolysaccharide (LPS) and initiate signaling cascades that lead to the production of inflammatory cytokines. Although these responses are initiated within hours, they can continue for at least 24 hours. The sustained response may be of particular relevance to diseases characterized by excessive inflammation. Kang et al. implicate a type-2 transmembrane protein, 4-1BBL (also called CD137L)--a member of the tumor necrosis factor (TNF) superfamily--in such sustained cytokine production by macrophages. The authors detected 4-1BBL in a two-hybrid screen for proteins that interacted with the intracellular domain of TLR4 and further supported possible interaction of the proteins in human embryonic kidney 293T cells overexpressing tagged versions of the proteins. Mouse macrophages stimulated with LPS to activate TLRs rapidly expressed 4-1BBL at the cell surface, and macrophages lacking 4-1BBL that were treated with LPS produced smaller amounts of TNF, interleukin-6 (IL-6), and IL-12 24 hours after stimulation than did similarly treated wild-type cells. More rapid cytokine production (within the first few hours) in response to LPS was similar in both cell types. The 4-1BBL acts as a ligand for the receptor 4-1BB in T cells, but 4-1BB appeared not to be required for the promotion of cytokine production by 4-1BBL because macrophages lacking 4-1BB produced normal amounts of TNF after stimulation with LPS. The authors suggest that 4-1BBL may produce a signal itself on the basis of experiments in which 4-1BBL was cross-linked on the surface of macrophages, perhaps as part of a complex with TLRs. In wild-type macrophages, the authors found evidence for two sequential signaling complexes containing TLR4. Early on, immunoprecipitation showed association of TLR4 with the signaling adaptor MyD88. Later, they saw association of TLR4 and 4-1BBL, but no association of 4-1BBL and MyD88 was detected. The more persistent complex with 4-1BBL, the authors note, may be a useful target for strategies aimed at treatment of inflammatory diseases Y. J. Kang, S. O. Kim, S. Shimada, M. Otsuka, A. Seit-Nebi, B. S. Kwon, T. H. Watts, J. Han, Cell surface 4-1BBL mediates sequential signaling pathways ‘downstream’ of TLR and is required for sustained TNF production in macrophages. Nat. Immunol. 8, 601-609 (2007). [PubMed]