title: Hypoxia inducible factor-1α mediates iron uptake which induces inflammatory response in amoeboid microglial cells in developing periventricular white matter through MAP kinase pathway.
abstract: Iron accumulation occurs in tissues such as periventricular white matter (PWM) in response to hypoxic injuries, and microglial cells sequester excess iron following hypoxic exposure. As hypoxia has a role in altering the expression of proteins involved in iron regulation, this study was aimed at examining the interaction between hypoxia inducible factor (HIF)-1α and proteins involved in iron transport in microglial cells, and evaluating the mechanistic action of deferoxamine and KC7F2 (an inhibitor of HIF-1α) in iron mediated hypoxic injury. Treating the microglial cultures with KC7F2, led to decreased expression of transferrin receptor and divalent metal transporter-1. Administration of deferoxamine or KC7F2 to hypoxic microglial cells enhanced extracellular signal-regulated kinase (ERK) phosphorylation (p-ERK), but decreased the phosphorylation of p38 (p-p38). The increased p-ERK further phosphorylated the cAMP response element-binding protein (p-CREB) which in turn may have resulted in the increased mitogen activated protein kinase (MAPK) phosphatase 1 (MKP1), known to dephosphorylate MAPKs. Consistent with the decrease in p-p38, the production of pro-inflammatory cytokines TNF-α and IL-1β was reduced in hypoxic microglia treated with deferoxamine and SB 202190, an inhibitor for p38. This suggests that the anti-inflammatory effect exhibited by deferoxamine is by inhibition of p-p38 induced inflammation through the pERK-pCREB-MKP1 pathway, whereas that of KC7F2 requires further investigation. The present results suggest that HIF-1α may mediate iron accumulation in hypoxic microglia and KC7F2, similar to deferoxamine, might provide limited protection against iron induced PWMD.
authors.affiliation: Department of Anatomy, MD10, 4 Medical Drive, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.
authors.forename: Gurugirijha
authors.initials: G
authors.lastname: Rathnasamy
authors.affiliation: Department of Anatomy, MD10, 4 Medical Drive, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.
authors.forename: Eng-Ang
authors.initials: EA
authors.lastname: Ling
authors.affiliation: Department of Anatomy, MD10, 4 Medical Drive, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore. Electronic address: antkaurc@nus.edu.sg.
authors.forename: Charanjit
authors.initials: C
authors.lastname: Kaur
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004220:Disulfides / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011990:Receptors, Transferrin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D003676:Deferoxamine; D004220:Disulfides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D007501:Iron; D011990:Receptors, Transferrin; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D000099236:Solute Carrier Family 11, Member 2; C497444:Hif1a protein, rat; C545729:KC7F2 compound
keywords: Cytokines; Deferoxamine; HIF-1α; Hypoxia; Iron; KC7F2; MAPKs; Microglia