Clarithromycin attenuates the expression of monocyte chemoattractant protein-1 by activating toll-like receptor 4 in human mesangial cells.
BACKGROUND
Signaling pathways induced by the activation of renal toll-like receptor 4 (TLR4) play a pivotal role in chronic kidney disease (CKD). Some recent studies suggested that clarithromycin (CAM), a 14-membered ring macrolide, exerts renoprotective effects by suppressing proinflammatory chemokines. However, its beneficial effects on signaling pathways through renal TLR4 activation are unknown.


METHODS
Cultured human mesangial cells (MCs) were treated with lipopolysaccharide (LPS). Expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and interleukin-8 (IL-8/CXCL8) was analyzed by quantitative RT-PCR and enzyme-linked immunosorbent assay. Signaling pathways affected by CAM were determined by examining the activation of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) by performing western blotting.


RESULTS
CAM inhibited both the mRNA and protein expression of MCP-1 without cell injury but did not affect those expressions of IL-8 in LPS-stimulated MCs. Interestingly, CAM decreased p38 MAPK activation by inhibiting phosphorylation but did not affect NF-κB activation.


CONCLUSIONS
Our results indicated that CAM exerted renoprotective effects by suppression of p38 MAPK activity and by decreasing the expression of MCP-1 in LPS-stimulated MCs. Given the implication of TLR4 signaling in CKD, CAM may be a potential treatment of choice for CKD.
Department of Pediatrics, Hirosaki University Hospital, Hirosaki University, Hirosaki, 036-8563, Japan.
Koji
K
Tsugawa
Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki University, Hirosaki, 036-8562, Japan.
Tadaatsu
T
Imaizumi
Department of Pediatrics, Hirosaki University Hospital, Hirosaki University, Hirosaki, 036-8563, Japan.
Shojiro
S
Watanabe
Department of Pediatrics, Hirosaki University Hospital, Hirosaki University, Hirosaki, 036-8563, Japan.
Kazushi
K
Tsuruga
Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki University, Hirosaki, 036-8562, Japan.
Hidemi
H
Yoshida
Department of Pediatrics, Hirosaki University Hospital, Hirosaki University, Hirosaki, 036-8563, Japan. hirotana@hirosaki-u.ac.jp.|Department of School Health Science, Faculty of Education, Hirosaki University, Hirosaki, 036-8560, Japan. hirotana@hirosaki-u.ac.jp.
Hiroshi
http://orcid.org/0000-0001-7057-813X
H
Tanaka
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D017291:Clarithromycin / Q000494:pharmacology*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D020011:Protective Agents; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D017291:Clarithromycin
Clarithromycin; Mesangial cells; Monocyte chemoattractant protein-1; Toll-like receptor 4