Ferritin levels increased in Hemin treated THP1 cells and decreased when cells were treated with tin protoporphyrin (SnPP) IX inaddtion to hemin, suggesting that HO-1 induction leads to intracellular iron accumulation. Treatment with hepcidin also restored HIV-1 inhibition in hemin treated THP-1 cells. Stable ferroportin knock-down prevented HIV-1 inhibition in THP-1 cells. In heme-treated THP-1 cells, mRNA expression of ferroportin, p21, SAMHD1, hypoxia-induced factor (HIF)-1α, and IKBα and NF-κB inhibitor was increased and CDK2 expression decreased. Specific gene knock-downs were generated in THP-1 cells using lentivirus expressing gene-targeted shRNAs. Gene expression and protein expression analysis was carried out using RNA and protein isolated from hemin treated and untreated cells using RT PCR western blot respectively. One round HIV-1 infection was analyzed in THP-1 cells infected with VSVg-pseudotyped HIV-1 expressing luciferase. We also analyzed SAM domain and HD domain-containing protein 1 (SAMHD1) as it was shown to be regulated by CDK2 and p21. We analyzed the effect of heme on HIV-1 infection in macrophages and the contribution of heme and iron regulatory proteins including HO-1, ferroportin and hepcidin and cell cycle regulatory cell cycle dependent kinase 2 (CDK2) and p21, which are deregulated by iron depletion. Iron depletion by iron chelators or through the expression of ferroportin, an iron export protein, inhibited HIV-1. LPS-treated human macrophages express HO-1 which may protect them against HIV-1 infection through the production of MIP1α, MIP1β and LD78β chemokines that decrease CCR5 expression. Heme oxygenase-1 (HO-1) induction by hemin inhibits HIV-1 infection in cultured macrophages and T-cells and also in HIV-1 infected humanized mice via a protein kinase C-dependent pathway (reviewed in ).
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