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

Masatoshi Takeiri, Miyuki Tachibana, Ayumi Kaneda, Ayumi Ito, Yuichi Ishikawa, Shigeru Nishiyama, Ryoichi Goto, Kenichiro Yamashita, Susumu Shibasaki, Gentaro Hirokata, Michitaka Ozaki, Satoru Todo, Kazuo Umezawa

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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.

Original languageEnglish
Pages (from-to)879-888
Number of pages10
JournalInflammation Research
Volume60
Issue number9
DOIs
Publication statusPublished - 09-2011

All Science Journal Classification (ASJC) codes

  • Immunology
  • Pharmacology

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    Takeiri, M., Tachibana, M., Kaneda, A., Ito, A., Ishikawa, Y., Nishiyama, S., Goto, R., Yamashita, K., Shibasaki, S., Hirokata, G., Ozaki, M., Todo, S., & Umezawa, K. (2011). Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone. Inflammation Research, 60(9), 879-888. https://doi.org/10.1007/s00011-011-0348-z