Kang Young Jun, Kim Sung Ouk, Shimada Shigeki, Otsuka Motoyuki, Seit-Nebi Alim, Kwon Byoung S, Watts Tania H, Han Jiahuai
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nat Immunol. 2007 Jun;8(6):601-9. doi: 10.1038/ni1471. Epub 2007 May 13.
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.
巨噬细胞上Toll样受体（TLR）的刺激会触发细胞因子肿瘤坏死因子（TNF）的产生。TNF的产生在TLR刺激后1小时内发生，并持续1天。在此，我们记录了TNF家族成员4-1BB配体（4-1BBL）在维持TLR诱导的TNF产生中的作用。TLR信号传导诱导4-1BBL，并且4-1BBL与巨噬细胞表面的TLR相互作用。4-1BBL对TNF产生的影响独立于其受体（4-1BB），并且不需要衔接蛋白MyD88或TRIF。它不影响TLR4诱导的转录因子NF-κB的激活（早期反应），但TLR4诱导的转录因子CREB和C/EBP的激活（晚期事件）则需要它。脂多糖刺激后第一小时内出现短暂的TLR4-MyD88复合物，脂多糖刺激后2小时至8小时之间检测到TLR4-4-1BBL相互作用。我们的结果表明，两种不同的TLR4复合物依次形成并选择性地控制早期和晚期TNF的产生。
