title: Heme: a novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms.
abstract: This study examined the effect of hemin on the expression of heme oxygenase-1 (HO-1) and monocyte chemoattractant protein-1 (MCP-1) in immortalized rat proximal tubular epithelial cells (IRPTCs). Hemin elicited a dose- and time-dependent induction of HO-1 and MCP-1 mRNA. HO activity contributed to MCP-1 mRNA expression at early time points (4-6 h) because inhibition of HO activity by zinc protoporphyrin (ZnPP) prevented hemin-induced expression of MCP-1 mRNA. Catalytically active intracellular iron was markedly increased in hemin-treated IRPTCs and contributed to the induction of HO-1 and MCP-1 mRNA because an iron chelator blocked hemin-induced upregulation of both genes, whereas a cell-permeant form of iron directly induced these genes. N-acetylcysteine completely blocked hemin-induced expression of HO-1 and MCP-1 mRNA, thereby providing added evidence for redox regulation of expression of these genes. The redox-sensitive transcription factor NF-kappaB was recruited in hemin-induced upregulation of MCP-1 because two different compounds that abrogate the activation of NF-kappaB (TPCK and BAY 11-7082) completely blocked hemin-induced upregulation of MCP-1 mRNA. In contrast to this HO-mediated induction of MCP-1 through redox-sensitive, iron-dependent, and NF-kappaB-involved pathways observed after 4-6 h, hemin also elicited a delayed induction of MCP-1 at 18 h through HO-independent pathways. We conclude that hemin is a potent inducer of MCP-1 in IRPTCs: HO-dependent, heme-degrading pathways lead to an early, robust, and self-remitting induction of MCP-1, whereas HO-independent mechanisms lead to a delayed expression of MCP-1.
authors.affiliation: Division of Nephrology, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA.
authors.forename: Sharan K R
authors.initials: SK
authors.lastname: Kanakiriya
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Croatt
authors.forename: Jill J
authors.initials: JJ
authors.lastname: Haggard
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
authors.forename: Shiow-Shih
authors.initials: SS
authors.lastname: Tang
authors.forename: Jawed
authors.initials: J
authors.lastname: Alam
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018932:Chemokine CCL2; D012333:RNA, Messenger; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1