Deferoxamine synergistically enhances iron-mediated AP-1 activation: a showcase of the interplay between extracellular-signal-regulated kinase and tyrosine phosphatase.
Deferoxamine (DFO) is a drug widely used for iron overload treatment to reduce body iron burden. In the present study, it was shown in mouse epidermal JB6 cells that all iron compounds transiently induced extracellular signal-regulated kinases (ERK) phosphorylation, whereas DFO further enhanced ERK phosphorylation over long periods. The ERK phosphorylation by DFO treatment appears to be due to the inhibition of MAPK phosphatases (MKP) by DFO. The combined effects of iron-initiated MAPK activation and DFO-mediated MKP inhibition resulted in a synergistic enhancement on AP-1 activities. The results indicate that the interplay between MAPK and MKP is important in regulating the extent of AP-1 activation. It is known that administration of DFO in iron overload patients often results in allergic responses at the injection sites. The results suggest that this synergistic AP-1 activation might play a role in DFO-induced skin immune responses of iron overload patients.
Huang
Xi
X
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10016, USA. xi.huang@med.nyu.edu
Dai
Jisen
J
Huang
Chuanshu
C
Zhang
Qi
Q
Bhanot
Opinder
O
Pelle
Edward
E
D000818:Animals; D002460:Cell Line; D003676:Deferoxamine / Q000494:pharmacology*; D007107:Immune System; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D017262:Siderophores / Q000494:pharmacology; D012867:Skin / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry
D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D017262:Siderophores; D018808:Transcription Factor AP-1; D014443:Tyrosine; D007501:Iron; D048052:Mitogen-Activated Protein Kinase 3; D017027:Protein Tyrosine Phosphatases; D003676:Deferoxamine