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

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.

Upregulation of heme oxygenase 1 (HO-1) attenuates kidney damage, oxidative stress and inflammatory reaction during renal ischemia/reperfusion injury

“…Also, it has been reported that, HO-1 upregulation attenuated nuclear factor-κB-induced inflammation in kidney tissues (Elmarakby et al 2012;Ndisang and Jadhav 2014;Liu et al 2015). Finally, previous studies reported HO-1-independent mechanisms for the protective effects of CoPP such as induction of P2X7 receptor activation, COX-2 expression and PIAS1 breakdown which is controlled by PI3K, Akt, and glycogen synthase kinase 3α/β (GSK3α/β) signaling pathways in microglial cells (Lin et al 2016).…”

“…Kusmic et al (2014) demonstrated that upregulation of HO-1 by cobalt protoporphyrin (CoPP) improved the animal mortality and ventricular remodeling and preserved connexin 43 expression in myocardial infarction in rats. It has been also shown that the use of CoPP diminished lipopolysaccharide (LPS)/interleukin 13 (IL-13)-prompted microglial death (Fu et al 2015;Lin et al 2016). So, we hypothesized that upregulation of HO-1 by CoPP in kidney could protect it against renal I/R.…”

Cobalt-protoporphyrin enhances heme oxygenase 1 expression and attenuates liver ischemia/reperfusion injury by inhibiting apoptosis

“…Cobalt-protoporphyrin (CoPP) is considered to be the most effective metalloporphyrin inducer of HO-1 (1,7,8). The present study investigated the anti-apoptotic mechanisms underlying HO-1-induced cytoprotection using CoPP and the HO-1 inhibitor zinc-protoporphyrin (ZnPP) (9) in a mouse model of liver I/R injury.…”

SIRT1 activation by minocycline on regulation of microglial polarization homeostasis

“…Transfection with SIRT1 siRNA abrogated SIRT1 expression ( Figure 2D ) and attenuated the acetyl-p53 levels in microglial cells ( Figure 2E ). Our previous study results have showed that PIAS1 is a regulator of the inflammatory process in microglia [ 50 ]. Treatment of microglial cells with CAY downregulated PIAS1 expression in a time-dependent manner ( Figure 2B ).…”

“…The protein inhibitor of activated stat (PIAS) 1 was initially identified as a suppressor of interferon-dependent transcription [ 74 ]. We previously reported that PIAS1 degradation is involved in microglial activation and proinflammatory expression [ 50 ]. Both PIAS1 and PIASy promote the SUMOylation and transcriptional activity of p53 [ 75 , 76 ].…”