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Tacrolimus down-regulates chemokine expressions on rheumatoid synovial fibroblasts: screening by a DNA microarray

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Abstract

Objective

Although the effects of tacrolimus on T cells are well-known, direct effects on rheumatoid synovial fibroblasts (RSF) remain unclear. We studied the effects of tacrolimus on RSF by a DNA microarray analysis.

Materials and methods

Tacrolimus and interleukin (IL)-1β were added to cultured RSF. Total RNA was prepared from the cells and the gene expression profile was analyzed by a DNA microarray screening system. mRNA expressions influenced by tacrolimus in the screening system were confirmed by real-time PCR. The effects of tacrolimus on nuclear translocation of nuclear factor-κB (NF-κB) were also examined.

Results

The mRNA expressions of CCL3, CCL4, and CXCL8 were up-regulated by IL-1β and down-regulated by tacrolimus. The levels of these IL-1β-induced chemokines in culture supernatant were decreased by a therapeutic concentration of tacrolimus. Tumor necrosis factor-α as well as IL-1β induced these chemokines, while tacrolimus inhibited their production and mRNA expression. Chemotaxis of polymorphonuclear cells in response to IL-1β was also inhibited by tacrolimus. Nuclear translocation of p50 and p65 NF-κB in response to IL-1β was decreased by tacrolimus.

Conclusion

IL-1β-induced chemokine expressions were down-regulated by tacrolimus, suggesting that tacrolimus exerts its anti-inflammatory effect partly through inhibiting chemokine production by RSF.

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Acknowledgments

This work was supported in part by a Project Research Grant (20-12) and Dr. Takeshi Yanase’s grant from Toho University School of Medicine to K.K.; Heisei 20 and 23 Strategic Research Foundation Grants from the Japanese Ministry of Education, Culture, Sports, Science & Technology to Toho University; Grants from Japan Society for the Promotion of Science (20591177, 23591449) to S.K.; and Grants from Nakatomi Foundation and Takeda Science Foundation to N.K. We wish to thank Ms. Sonoko Sakurai for secretarial assistance.

Conflict of interest

S.K. has received honoraria for lectures and research grants from Astellas Pharma Inc. (Tokyo, Japan), the manufacturer of tacrolimus. The other authors declare no conflict of interest.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan

    Kanako Kitahara, Natsuko Kusunoki & Shinichi Kawai

  2. Department of Orthopedics, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan

    Hiroshi Takahashi & Kazuaki Tsuchiya

Authors
  1. Kanako Kitahara
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  2. Natsuko Kusunoki
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  3. Hiroshi Takahashi
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  4. Kazuaki Tsuchiya
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  5. Shinichi Kawai
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Corresponding author

Correspondence to Shinichi Kawai.

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Responsible Editor: Ikuo Morita.

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Kitahara, K., Kusunoki, N., Takahashi, H. et al. Tacrolimus down-regulates chemokine expressions on rheumatoid synovial fibroblasts: screening by a DNA microarray. Inflamm. Res. 61, 1385–1394 (2012). https://doi.org/10.1007/s00011-012-0541-8

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  • DOI: https://doi.org/10.1007/s00011-012-0541-8

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