Activation of p38, ERK1/2 and NIK pathways is required for IL-1beta and TNF-alpha-induced chemokine expression in human retinal pigment epithelial cells.
Chemokine secretion by human retinal pigment epithelium (hRPE) in response to IL-1beta and TNF-alpha occurs in infectious and noninfectious retinal diseases. In this study, the roles of p38 kinase and extracellular signal-regulated kinase (ERK) signaling pathways were investigated for IL-1beta- or TNF-alpha-induced IL-8 and MCP-1 secretion by hRPE cells. Treatment of hRPE cells with IL-1beta or TNF-alpha caused increased steady-state IL-8 and MCP-1 mRNA levels and protein secretion. Stimulation of hRPE with IL-1beta and TNF-alpha resulted in degradation of IkappaB-alpha, nuclear translocation of NF-kappaB, and prominent increases in p38 and ERK1/2 phosphorylation for as little as 3 min. The induced IL-8 and MCP-1 mRNA and proteins were partially suppressed by U0126, a specific MEK inhibitor, and by SB202190, a selective p38 inhibitor. This induction was completely blocked by simultaneous administration of the two drugs or by incubation with inhibitors for activation of NF-kappaB such as BAY11-7085, CAPE, and parthenolide. These results suggest that co-activation of MEK/ERK and p38 pathways as well as activation of NIK pathway are essential for IL-1beta- and TNF-alpha-stimulation of IL-8 and MCP-1 gene expression in hRPE cells. Furthermore, co-administration of U0126 and SB202190 did not affect the induced degradation of IkappaB-alpha and NF-kappaB nuclear translocation, indicating that NF-kappaB is activated by IL-1beta and TNF-alpha independently of activation of MEK/MAPK and p38 pathways in hRPE cells.
Bian
Z M
ZM
Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, U.S.A.
Elner
S G
SG
Yoshida
A
A
Kunkel
S L
SL
Su
J
J
Elner
V M
VM
D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology; D007124:Immunoenzyme Techniques; D007375:Interleukin-1 / Q000502:physiology*; D016209:Interleukin-8 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D010857:Pigment Epithelium of Eye / Q000502:physiology*; D012160:Retina / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D002070:Butadienes; D018932:Chemokine CCL2; D018925:Chemokines; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D009570:Nitriles; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases