SOCS3 modulates interleukin-6R signaling preference in dermal fibroblasts.
OBJECTIVE
This study aims to investigate the mechanisms in the apparent preference for mitogen-activated protein kinase /ERK signaling through interleukin (IL)-6R in dermal fibroblasts.


METHODS
Dermal fibroblasts isolated from IL-6KO mice were pretreated with specific ERK or STAT3 chemical inhibitors or SOCS3 specific siRNA and treated with rmIL-6. Phosphorylation was monitored via enzyme-linked immunosorbent assay or immunohistology. SOCS3 interaction with p120Ras-Gap was examined by co-immunoprecipitation and Western blot. Expression of MMP2 mRNA was assessed via real-time quantitative polymerase chain reaction.


RESULTS
A dose response phosphorylation of ERK1/2 occurred while no STAT3 activation (p-Tyr705) was induced after IL-6 treatment, despite an increase in Ser727 phosphorylation. Inhibition of STAT3 in fibroblasts potentiated IL-6R induced ERK phosphorylation and vice versa. Phosphorylated SOCS3 and p120 RasGAP co-immunoprecipitated in response to IL-6 treatment. SOCS3 siRNA knockdown allowed STAT3 phosphorylation after rmIL-6 treatment. Chemical inhibition of IL-6R signaling altered the IL-6 modulated mRNA expression of MMP-2.


CONCLUSIONS
SOCS3 interaction with p120 Ras-Gap plays a role in determining the preference for IL-6R signaling through ERK in dermal fibroblasts. This study provides insight into the pleiotropic nature of IL-6 and the selective signaling mechanism elicited by the IL-6R system in dermal fibroblasts. It may further indicate a method for manipulation of IL-6R function.
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
Lerin R
LR
Luckett-Chastain
Michael A
MA
Ihnat
Bethany M
BM
Mickle-Kawar
Randle Michael
RM
Gallucci
D000818:Animals; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020729:p120 GTPase Activating Protein / Q000378:metabolism
D015850:Interleukin-6; D034741:RNA, Small Interfering; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D020729:p120 GTPase Activating Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse