Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages.
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.
Kang
Young Jun
YJ
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Kim
Sung Ouk
SO
Shimada
Shigeki
S
Otsuka
Motoyuki
M
Seit-Nebi
Alim
A
Kwon
Byoung S
BS
Watts
Tania H
TH
Han
Jiahuai
J
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*
D053330:4-1BB Ligand; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D048069:Tumor Necrosis Factors