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KMID : 0624620230560060359
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BMB Reports
2023 Volume.56 No. 6 p.359 ~ p.364
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Recombinant human KAI1/CD82 attenuates M1 macrophage polarization on LPS-stimulated RAW264.7 cells via blocking TLR4/JNK/NF-κB signal pathway
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Lee Hye-Sook
Han Jung-Hwa
An Kang-Bin
Kang Yun-Jeong
Landon L. Chan
Heo Ji-Hye
Choi Byung-Hyun
Kim Jae-Joon
Kim Seo-Rin
Lee Soo-Yong
Hur Jin
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Abstract
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KAI1/CD82, a membrane tetraspanin protein, can prevent various cancers and retinal disorders through its anti-angiogenic and anti-metastatic capacity. However, little is known about its anti-inflammatory effect and molecular mechanism. Therefore, the present study aimed to inLPSvestigate effect of a recombinant protein of the large extracellular domain of human KAI1 (Gly 111-Leu 228, rhKAI1) on lipopolysaccharides (LPS)-stimulated RAW264.7 macrophage-like cells and mouse bone marrow-derived macrophages (BMDM) and to identify its underlying mechanism. Our data showed that rhKAI1 suppressed expression levels of classically macrophages (M1) phenotype-related surface markers F4/80+CD86+ in LPS-stimulated BMDM and RAW264.7 cells. In addition, LPS markedly increased mRNA expression and release levels of pro-inflammatory cytokines and mediators such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α, cyclooxygenase-2, nitric oxide and prostaglandin E2, whereas these increases were substantially down-regulated by rhKAI1. Furthermore, LPS strongly increased expression of NF-κB p65 in the nuclei and phosphorylation of ERK, JNK, and p38 MAPK. However, nuclear translocation of NF-κB p65 and phosphorylation of JNK were greatly reversed in the presence of rhKAI1. Especially, rhKAI1 markedly suppressed expression of toll-like receptor (TLR4) and prevented binding of LPS with TLR4 through molecular docking predict analysis. Importantly, Glu 214 of rhKAI1 residue strongly interacted with Lys 360 of TLR4 residue, with a binding distance of 2.9 A. Taken together, these findings suggest that rhKAI1 has an anti-inflammatory effect on LPS-polarized macrophages by interacting with TLR4 and down-regulating the JNK/NF-κB signaling pathway.
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KEYWORD
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Inflammation, JNK/NF-κB signaling pathway, KAI1, M1 macrophage polarization, TLR4
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