Skip to main content
SpringerLink
Log in

Clarithromycin attenuates the expression of monocyte chemoattractant protein-1 by activating toll-like receptor 4 in human mesangial cells

  • Original Article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

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.

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Robson MG. Toll-like receptors and renal disease. Nephron Exp Nephrol. 2009;113:e1–7.

    Article  CAS  PubMed  Google Scholar 

  2. Coppo R, Amore A, Peruzzi L, Vergano L, Camilla R. Innate immunity and IgA nephropathy. J Nephrol. 2010;23:626–32.

    PubMed  Google Scholar 

  3. Lepenies J, Eardley KS, Kienitz T, Hewison M, Ihl T, Stewart PM, Cockwell P, Quinkler M. Renal TLR4 mRNA expression correlates with inflammatory marker MCP-1 and profibrotic molecule TGF-β1, in patients with chronic kidney disease. Nephron Clin Pract. 2011;119:c97–104.

    Article  CAS  PubMed  Google Scholar 

  4. Migliorini A, Ebid R, Scherbaum CR, Anders HJ. The danger control concept in kidney disease: mesangial cells. J Nephrol. 2013;26:437–49.

    Article  CAS  PubMed  Google Scholar 

  5. Imaizumi T, Tanaka H, Matsumiya T, Yoshida H, Tanji K, Tsuruga K, Oki E, Aizawa-Yashiro T, Ito E, Satoh K. Retinoic acid-inducible gene-I is induced by double-stranded RNA and regulates the expression of CC chemokine ligand (CCL) 5 in human mesangial cells. Nephrol Dial Transplant. 2010;25:3534–9.

    Article  CAS  PubMed  Google Scholar 

  6. Aizawa-Yashiro T, Imaizumi T, Tsuruga K, Watanabe S, Matsumiya T, Hayakari R, Yoshida H, Satoh K, Ito E, Tanaka H. Glomerular expression of fractalkine is induced by polyinosinic-polycytidylic acid in human mesangial cells: possible involvement of fractalkine after viral infection. Pediatr Res. 2013;73:180–6.

    Article  CAS  PubMed  Google Scholar 

  7. Imaizumi T, Aizawa-Yashiro T, Watanabe S, Matsumiya T, Yoshida H, Tatsuta T, Xing F, Meng P, Hayakari R, Tsuruga K, Tanaka H. TLR4 signaling induces retinoic acid inducible gene-I and melanoma differentiation-associated gene 5 in mesangial cells. J Nephrol. 2013;26:886–93.

    Article  PubMed  Google Scholar 

  8. Tanaka H, Imaizumi T. Inflammatory chemokine expression via toll-like receptor 3 signaling in normal human mesangial cells. Clin Dev Immunol. 2013;2013:984708. doi:10.1155/2013/9847028.

    PubMed  PubMed Central  Google Scholar 

  9. Imaizumi T, Aizawa T, Hayakari R, Xing F, Meng P, Tsuruga K, Matsumiya T, Yoshida H, Wang L, Tatsuta T, Tanaka H. Tumor necrosis factor-α synergistically enhances polyinosinic-polycytidylic acid-induced toll-like receptor 3 signaling in cultured normal human mesangial cells: possible involvement in the pathogenesis of lupus nephritis. Clin Exp Nephrol. 2015;19:75–81.

    Article  CAS  PubMed  Google Scholar 

  10. Imaizumi T, Aizawa T, Segawa C, Shimada M, Tsuruga K, Kawaguchi S, Matsumiya T, Yoshida H, Joh K, Tanaka H. Toll-like receptor 3 signaling contributes to the expression of a neutrophil chemoattractant, CXCL1, in human mesangial cells. Clin Exp Nephrol. 2015;19:761–70.

    Article  CAS  PubMed  Google Scholar 

  11. Tanaka H, Imaizumi T. Mesangial viral and psuedoviral immunity: possible involvement in the pathogenesis of pediatric-onset active lupus nephritis. J Arthritis. 2015;4:183. doi:10.4172/2167-7921.1000183.

    Article  Google Scholar 

  12. Friedlander AL, Albert RK. Chronic macrolide therapy in inflammatory airways diseases. Chest. 2010;138:1202–12.

    Article  CAS  PubMed  Google Scholar 

  13. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respr Crit Care Med. 2008;177:148–55.

    Article  CAS  Google Scholar 

  14. Yasutomi M, Ohshima Y, Omata N, Yamada A, Iwasaki H, Urasaki Y, Mayumi M. Erythromycin differentially inhibits lipopolysaccharide- or poly IC-induced but not peptidoglycan-induced activation of human monocyte-derived dendritic cells. J Immunol. 2005;175:8069–76.

    Article  CAS  PubMed  Google Scholar 

  15. Tone A, Shikata K, Sasaki M, Ohga S, Yozai K, Nishishita S, Usui H, Nagase R, Ogawa D, Okada S, Shikata Y, Wada J, Makino H. Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats. Diabetologia. 2005;48:2402–11.

    Article  CAS  PubMed  Google Scholar 

  16. Yamabe H, Shimada M, Kaizuka M, Nakamura M, Kumasaka R, Murakami R, Fujita T, Nakamura N, Osawa H, Okumura K. Roxithromycin inhibits transforming growth factor-β production by cultured human mesangial cells. Nephrology (Carlton). 2006;11:524–30.

    Article  CAS  Google Scholar 

  17. Tone A, Shikata K, Nakagawa K, Hashimoto M, Makino H. Renoprotective effects of clarithromycin via reduction of urinary MCP-1 levels in type 2 diabetic patients. Clin Exp Nephrol. 2011;15:79–85.

    Article  CAS  PubMed  Google Scholar 

  18. Park JY, Kim HY, Lee JY, Kim KH, Jang MK, Lee JH, Yoo JY, Han DS, Hahm JS. Macrolide-affected Toll-like receptor 4 expression from Helicobacter pylori-infected monocytes does not modify interleukin-8 production. FEMS Immunol Med Microbiol. 2005;44:171–6.

    Article  CAS  PubMed  Google Scholar 

  19. Lim BJ, Lee D, Hong SW, Jeong HJ. Toll-like receptor 4 signaling is involved in IgA-stimulated mesangial cell activation. Yonsei Med J. 2011;54:610–5.

    Article  Google Scholar 

  20. Tomita H, Osanai T, Toki T, Maeda N, Murakami R, Chen Z, Yamabe H, Osawa H, Yasujima M, Okumura K. Roxithromycin is an inhibitor of human coronary artery smooth muscle cells proliferation: a potential ability to prevent coronary heart disease. Atherosclerosis. 2005;182:87–95.

    Article  CAS  PubMed  Google Scholar 

  21. Aizawa T, Imaizumi T, Tsuruga K, Watanabe S, Kumagai N, Chiba Y, Yoshida H, Ito E, Tanaka H. Urinary fractalkine and monocyte chemoattractant protein-1 as possible predicators of disease activity of childhood glomerulonephritis. Tohoku J Exp Med. 2013;231:265–70.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Grants-in-Aid of the Japan Society for Promotion of Science (JSPS KAKENHI Grant Number 25461615 to H. T.).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Hirosaki University Hospital, Hirosaki University, Hirosaki, 036-8563, Japan

    Koji Tsugawa, Shojiro Watanabe, Kazushi Tsuruga & Hiroshi Tanaka

  2. Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki University, Hirosaki, 036-8562, Japan

    Tadaatsu Imaizumi & Hidemi Yoshida

  3. Department of School Health Science, Faculty of Education, Hirosaki University, Hirosaki, 036-8560, Japan

    Hiroshi Tanaka

Authors
  1. Koji Tsugawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tadaatsu Imaizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shojiro Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazushi Tsuruga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hidemi Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroshi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Tanaka.

Ethics declarations

This study was performed using only commercial-based materials. There were no human materials involving ethical matters.

Conflict of interest

The authors declare that they do not have any conflicts of interest related to this study.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsugawa, K., Imaizumi, T., Watanabe, S. et al. Clarithromycin attenuates the expression of monocyte chemoattractant protein-1 by activating toll-like receptor 4 in human mesangial cells. Clin Exp Nephrol 21, 573–578 (2017). https://doi.org/10.1007/s10157-016-1333-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-016-1333-1

Keywords

Search

Navigation