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Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone

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Abstract

Objective

We have previously synthesized a novel piperidine compound, 3-[(dodecylthiocarbonyl)methyl]glutarimide (DTCM-glutarimide), that inhibits LPS-induced NO production, and in the present research we studied further the anti-inflammatory activity of DTCM-glutarimide in a macrophage cell line and in mice bearing transplanted hearts.

Materials and methods

Mouse macrophage-like RAW264.7 cells were employed for the evaluation of cellular inflammatory activity. DTCM-glutarimide was synthesized in our laboratory. The AP-1 activity was measured by nuclear translocation and phosphorylation. For the heart transplantation experiment, male C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donor and recipient, respectively. DTCM-glutarimide was administered intraperitoneally.

Results

DTCM-glutarimide inhibited the LPS-induced expression of iNOS and COX-2 in macrophages; but, unexpectedly, it did not inhibit LPS-induced NF-κB activation. Instead, it inhibited the nuclear translocation of both c-Jun and c-Fos. It also inhibited LPS-induced c-Jun phosphorylation. Moreover, it inhibited the mixed lymphocyte reaction in primary cultures of mouse spleen cells; and furthermore, in mice it prolonged the graft survival in heart transplantation experiments.

Conclusion

The novel piperidine compound, DTCM-glutarimide, was found to be a new inhibitor of macrophage activation, inhibiting AP-1 activity. It also inhibited graft rejection in mice, and thus may be a candidate for an anti-inflammatory agent.

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Acknowledgments

This work was financially supported in part by grants from the program Grants-in-Aid for Scientific Research on Priority Areas of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT). It was also supported by a High-Tech Research Center Project for Private Universities: matching fund subsidy from MEXT, 2006–2011, and the Global Center of Excellence Program from MEXT, 2007–2012.

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Authors and Affiliations

  1. Center for Chemical Biology, School of Fundamental Science and Technology, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-0061, Japan

    Masatoshi Takeiri, Miyuki Tachibana, Ayumi Kaneda, Ayumi Ito, Yuichi Ishikawa, Shigeru Nishiyama & Kazuo Umezawa

  2. Department of Surgery, Hokkaido University School of Medicine, Sapporo, 060-8683, Japan

    Ryoichi Goto, Kenichiro Yamashita, Susumu Shibasaki, Gentaro Hirokata, Michitaka Ozaki & Satoru Todo

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  1. Masatoshi Takeiri
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Correspondence to Kazuo Umezawa.

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Takeiri, M., Tachibana, M., Kaneda, A. et al. Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone. Inflamm. Res. 60, 879–888 (2011). https://doi.org/10.1007/s00011-011-0348-z

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  • DOI: https://doi.org/10.1007/s00011-011-0348-z

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