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Cobalt Protoporphyrin Upregulates Cyclooxygenase-2 Expression Through a Heme Oxygenase-Independent Mechanism

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Abstract

Cobalt protoporphyrin (CoPP) is a potent HO-1 inducer and generally known to be an antioxidant in various cell types. Little is known about the CoPP-induced cyclooxygenase-2 (COX-2) expression and its downstream signaling in microglial cells. In current study, CoPP caused concentration- and time-dependent increases in COX-2 expression in microglial cells. Furthermore, activation of apoptosis signal-regulating kinase (ASK) 1/MAP kinase involved in CoPP-induced COX-2 expression in microglia. CoPP also induced P2X7 receptor activation, and treatment of P2X7 inhibitors effectively reduced CoPP-induced COX-2 expression. Protein inhibitor of activated STAT (PIAS) 1 is reported to be involved in modulating anti-inflammatory response through negative regulation of transcription factors. Interestingly, treatment with CoPP markedly induced PIAS1 degradation which is regulated by PI3K, Akt, and glycogen synthase kinase 3α/β (GSK3α/β) signaling pathways. These results suggest that CoPP induces COX-2 expression through activating P2X7 receptors and ASK1/MAP kinases as well as PIAS1 degradation signaling pathways. Our study provides a new insight into the regulatory effect of CoPP on neuroinflammation in microglial cells.

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Acknowledgments

This work is supported in part by grants from the National Science Council (NSC 102-2320-B-039-051-MY3, NSC 102-2320-B-039-026-MY3, NSC 103-2811-B-039-021, and NSC 104-2320-B-468-002), China Medical University (CMU102-ASIA-24), and Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002).

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The authors report no biomedical financial interests or potential conflicts of interest.

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    Authors and Affiliations

    1. Graduate Institute of Neural and Cognitive Sciences, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan

      Hsiao-Yun Lin, Chon-Haw Tsai & Dah-Yuu Lu

    2. Department of Neurology, China Medical University Hospital, Taichung, Taiwan

      Chon-Haw Tsai

    3. Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan

      Chingju Lin

    4. Department of Cell and Tissue Engineering, Changhua Christian Hospital, Changhua, Taiwan

      Wei-Lan Yeh

    5. Department of Biotechnology, Asia University, Taichung, Taiwan

      Cheng-Fang Tsai

    6. Department of Bioinformatics, Asia University, Taichung, Taiwan

      Pei-Chun Chang

    7. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan

      Ling-Hsuan Wu

    8. Department of Photonics and Communication Engineering, Asia University, Taichung, Taiwan

      Dah-Yuu Lu

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    Lin, HY., Tsai, CH., Lin, C. et al. Cobalt Protoporphyrin Upregulates Cyclooxygenase-2 Expression Through a Heme Oxygenase-Independent Mechanism. Mol Neurobiol 53, 4497–4508 (2016). https://doi.org/10.1007/s12035-015-9376-y

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