IL-1β Upregulates IL-8 Production in Human Müller Cells Through Activation of the p38 MAPK and ERK1/2 Signaling Pathways.
Diabetic retinopathy shares some similarity with chronic inflammation and Müller cells dysfunction may play an important role in its initiation and progression since these cells are thought to be a major source of inflammatory factors. The goal of this study was to examine the effect of cytokines on human retinal Müller cells and to understand the underlying signal transduction pathways regulating interleukin-8 (IL-8) expression. In this study, human MIO-M1 cells were treated with interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-8, vascular endothelial growth factor (VEGF), interferon-gamma (IFN-γ), glucose, or mannitol, followed by examination of their IL-8 protein and mRNA levels by Western blotting and PCR, respectively. After treatment with IL-1β, the levels of phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3) were measured. IL-8 was also measured by Western blotting and ELISA following Müller cell culture with IL-1β and specific inhibitors of the p38 MAPK, ERK1/2, JNK, or JAK2 pathways. The results showed that IL-1β was a potent inducer of IL-8 expression in MIO-M1 cells, although a relatively small increase was induced by TNF-α. IL-6, IL-8, VEGF, and IFN-γ did not modify IL-8 expression. Increase of IL-8 expression was accompanied by a significant increased phosphorylation of p38 MAPK, ERK, and JNK, but not of JAK2 and STAT3. Furthermore, inhibitors of p38 MAPK and MEK1/2, but not for JNK and JAK2, significantly inhibited IL-8 expression. In conclusion, IL-1β potently stimulates IL-8 expression in Müller cells mainly through the p38 MAPK and ERK1/2 pathways.
Department of Ophthalmology, The First Hospital, Jilin University, Changchun, Jilin, 130021, China.
Xiufen
X
Liu
Fei
F
Ye
Huabao
H
Xiong
Danning
D
Hu
G Astrid
GA
Limb
Tian
T
Xie
Liang
L
Peng
Wei
W
Yang
Yabin
Y
Sun
Mingming
M
Zhou
E
E
Song
David Y
DY
Zhang
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D053583:Interleukin-1beta; D016209:Interleukin-8; D048051:p38 Mitogen-Activated Protein Kinases