Direct Binding of Toll-Like Receptor 2 to Zymosan, and Zymosan-Induced NF-κB Activation and TNF-α Secretion Are Down-Regulated by Lung Collectin Surfactant Protein A

Abstract

The lung collectin surfactant protein A (SP-A) has been implicated in the regulation of pulmonary host defense and inflammation. Zymosan induces proinflammatory cytokines in immune cells. Toll-like receptor (TLR)2 has been shown to be involved in zymosan-induced signaling. We first investigated the interaction of TLR2 with zymosan. Zymosan cosedimented the soluble form of rTLR2 possessing the putative extracellular domain (sTLR2). sTLR2 directly bound to zymosan with an apparent binding constant of 48 nM. We next examined whether SP-A modulated zymosan-induced cellular responses. SP-A significantly attenuated zymosan-induced TNF-α secretion in RAW264.7 cells and alveolar macrophages in a concentration-dependent manner. Although zymosan failed to cosediment SP-A, SP-A significantly reduced zymosan-elicited NF-κB activation in TLR2-transfected human embryonic kidney 293 cells. Because we have shown that SP-A binds to sTLR2, we also examined whether SP-A affected the binding of sTLR2 to zymosan. SP-A significantly attenuated the direct binding of sTLR2 to zymosan in a concentration-dependent fashion. From these results, we conclude that 1) TLR2 directly binds zymosan, 2) SP-A can alter zymosan-TLR2 interaction, and 3) SP-A down-regulates TLR2-mediated signaling and TNF-α secretion stimulated by zymosan. This study supports an important role of SP-A in controlling pulmonary inflammation caused by microbial pathogens.

Toll-like Receptor

“…For example, surfactant protein A was shown to bind extracellular domain of TLR2 and down-regulate induction of NF-kB and TNF-a secretion, competing the same receptor with peptidoglycan and zymosan. 137,138 This suggests possible interaction between the different ligands, which can bind to same receptors, leading to modification of activated signal pathways depending type, amount and distribution of the ligands both in physiological and pathologic conditions. Complex of TLR-like molecule, RP105 and MD-1 can acts as TLR4 decoy receptor.…”

Innate immunity as orchestrator of stem cell mobilization

“…In support of this notion, TLR2 binds zymosan and TLR4 binds lipopolysaccharide. 93,94 However, the involvement of TLRs in stem cell mobilization requires further study.…”

Toll-like receptor signal transduction

“…For instance, whether TLRs can directly recognize their ligands as some studies suggest (Lien et al, 2000;Poltorak et al, 2000;Sato et al, 2003a) or whether an accessory molecule like MD2 or an intermediary similar to Drosophila extracellular protein Spatzle performs this function (Akashi et al, 2001;Medzhitov, 2001;Hoffman and Reichhart, 2002). The another intriguing question with TLRs is how the innate immune system manages to recognize synthetic CpG oligonucleotides and bacterial DNA against a possible background of host DNA set generated through trauma, apoptosis or other events that liberate host DNA inside the body.…”