Open Access

Carboxyamidotriazole exerts anti‑inflammatory activity in lipopolysaccharide‑induced RAW264.7 macrophages by inhibiting NF‑κB and MAPKs pathways

  • Authors:
    • Shan Lu
    • Mengyuan Duan
    • Zehao Guo
    • Yongting Zhou
    • Danwei Wu
    • Xiaojuan Zhang
    • Yicheng Wang
    • Caiying Ye
    • Rui Ju
    • Juan Li
    • Dechang Zhang
    • Lei Zhu
  • View Affiliations

  • Published online on: June 12, 2020     https://doi.org/10.3892/etm.2020.8889
  • Pages: 1455-1466
  • Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Carboxyamidotriazole (CAI), originally developed as a non-cytotoxic anti-cancer drug, was shown to have anti‑inflammatory activity according to recent studies in a number of animal models of inflammation. However, its mechanism of action has not been characterized. Therefore, the present study was performed to identify the anti‑inflammatory action of CAI in lipopolysaccharide (LPS)‑induced RAW 264.7 macrophages and to identify the signal transduction pathways involved. The in vitro results revealed that CAI had no direct effect on the activity of cyclooxygenase (COX), suggesting a different anti‑inflammatory mechanism compared with that of COX‑inhibiting non‑steroidal anti‑inflammatory drugs. Further investigation in RAW264.7 macrophages revealed that CAI decreased the production of nitric oxide via decreasing the LPS‑stimulated expression of inducible nitric oxide synthase, and downregulated both mRNA and protein expression levels of the cytokines tumor necrosis factor‑α, interleukin (IL)‑1β, and IL‑6. CAI also significantly reduced the increased DNA‑binding activity of nuclear factor (NF)‑κB induced by LPS stimulation. With respect to the mechanisms involved on NF‑κB activity, CAI exhibited suppression of the phosphorylation and degradation of the inhibitor of nuclear factor‑κBα (IκB), and decreased the phosphorylation levels of the p65 subunit and its subsequent nuclear translocation. In addition, CAI significantly decreased the phosphorylated forms of p38, JNK and ERK, which were increased following LPS stimulation, while the total expression levels of p38, JNK and ERK remained unaltered. The results in the present study indicate that CAI alleviates the inflammatory responses of RAW 264.7 macrophages in response to LPS stimulation via attenuating the activation of NF‑κB and MAPK signaling pathways and decreasing the levels of pro‑inflammatory mediators. This offers a novel perspective for understanding the anti‑inflammatory mechanism of CAI and suggests its potential use as a therapeutic treatment in inflammatory diseases with excessive macrophage activation.

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August-2020
Volume 20 Issue 2

Print ISSN: 1792-0981
Online ISSN:1792-1015

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APA
Lu, S., Duan, M., Guo, Z., Zhou, Y., Wu, D., Zhang, X. ... Zhu, L. (2020). Carboxyamidotriazole exerts anti‑inflammatory activity in lipopolysaccharide‑induced RAW264.7 macrophages by inhibiting NF‑κB and MAPKs pathways. Experimental and Therapeutic Medicine, 20, 1455-1466. https://doi.org/10.3892/etm.2020.8889
MLA
Lu, S., Duan, M., Guo, Z., Zhou, Y., Wu, D., Zhang, X., Wang, Y., Ye, C., Ju, R., Li, J., Zhang, D., Zhu, L."Carboxyamidotriazole exerts anti‑inflammatory activity in lipopolysaccharide‑induced RAW264.7 macrophages by inhibiting NF‑κB and MAPKs pathways". Experimental and Therapeutic Medicine 20.2 (2020): 1455-1466.
Chicago
Lu, S., Duan, M., Guo, Z., Zhou, Y., Wu, D., Zhang, X., Wang, Y., Ye, C., Ju, R., Li, J., Zhang, D., Zhu, L."Carboxyamidotriazole exerts anti‑inflammatory activity in lipopolysaccharide‑induced RAW264.7 macrophages by inhibiting NF‑κB and MAPKs pathways". Experimental and Therapeutic Medicine 20, no. 2 (2020): 1455-1466. https://doi.org/10.3892/etm.2020.8889