title: Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages.
abstract: The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of the cytokine tumor necrosis factor (TNF). TNF production occurs within 1 h of TLR stimulation and is sustained for 1 d. Here we document a function for the TNF family member 4-1BB ligand (4-1BBL) in sustaining TLR-induced TNF production. TLR signaling induced 4-1BBL, and 4-1BBL interacted with TLRs on the macrophage surface. The influence of 4-1BBL on TNF production was independent of its receptor (4-1BB) and did not require the adaptors MyD88 or TRIF. It did not influence TLR4-induced activation of transcription factor NF-kappaB (an early response) but was required for TLR4-induced activation of transcription factors CREB and C/EBP (a late event). Transient TLR4-MyD88 complexes appeared during the first hour after lipopolysaccharide stimulation, and TLR4-4-1BBL interactions were detected between 2 h and 8 h after lipopolysaccharide stimulation. Our results indicate that two different TLR4 complexes sequentially form and selectively control early and late TNF production.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
authors.forename: Sung Ouk
authors.initials: SO
authors.lastname: Kim
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shimada
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Alim
authors.initials: A
authors.lastname: Seit-Nebi
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
mesh_terms: D053330:4-1BB Ligand / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D015996:Survival Rate; D013997:Time Factors; D051193:Toll-Like Receptors / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000096:biosynthesis*
chemical_list: D053330:4-1BB Ligand; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D048069:Tumor Necrosis Factors