title: Carbon monoxide, a reaction product of heme oxygenase-1, suppresses the expression of C-reactive protein by endoplasmic reticulum stress through modulation of the unfolded protein response.
abstract: The expression of C-reactive protein (CRP) rises rapidly in response to inflammation. The endoplasmic reticulum (ER) stress has been reported to cause CRP expression. Carbon monoxide (CO), a reaction product of heme oxygenase, exerts anti-inflammatory effects. In this study, we aimed to examine the role of CO in modulating ER stress-induced CRP expression. In HepG2 cells, ER stress triggered by tunicamycin, thapsigargin and homocysteine markedly induced CRP expression and the activation of protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring transmembrane kinase/endonuclease 1α (IRE1α), activating transcription factor 6 (ATF6), and hepatocyte-specific cyclic AMP response element binding protein H (CREBH). A CO-releasing molecule (CORM) inhibited ER stress-induced CRP expression. While CORM attenuated ER stress-induced activation of IRE1α, ATF6 and CREBH, it augmented PERK activation, which was associated with its inhibition of CRP expression. CORM also inhibited CRP expression in response to the pro-inflammatory cytokine IL-6 that was found to induce ER stress response in HepG2 cells. Moreover, in mice treated with the ER stress inducer tunicamycin, CORM administration reduced serum levels of CRP and the expression of CRP mRNA in the liver. Collectively, our findings suggest that CO may attenuate ER stress-induced CRP expression through modulation of the unfolded protein response.
authors.affiliation: School of Biological Sciences, University of Ulsan, Meta-Inflammation Basic Research Laboratory, Ulsan 680-749, Republic of Korea.
authors.forename: Jihwa
authors.initials: J
authors.lastname: Chung
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Shin
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.forename: Hyun-Ock
authors.initials: HO
authors.lastname: Pae
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Hun-Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000096:biosynthesis*; D002248:Carbon Monoxide / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D014162:Transfection; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D002248:Carbon Monoxide; D002097:C-Reactive Protein; D051547:Heme Oxygenase-1