SOCS3 modulates interleukin-6R signaling preference in dermal fibroblasts

Area of Science:

• Cellular and Molecular Biology
• Immunology
• Dermatology

Background:

• Interleukin-6 (IL-6) is a pleiotropic cytokine with diverse cellular functions.
• IL-6 receptor (IL-6R) signaling involves complex pathways, including mitogen-activated protein kinase/ERK and Signal Transducer and Activator of Transcription 3 (STAT3).
• Understanding selective IL-6R signaling is crucial for deciphering its role in dermal fibroblast biology.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the preferential activation of ERK signaling over STAT3 by IL-6R in dermal fibroblasts.
• To elucidate the role of SOCS3 and its interaction with p120 Ras-Gap in modulating IL-6R signal transduction.

Main Methods:

• Dermal fibroblasts from IL-6 knockout (IL-6KO) mice were treated with rmIL-6 after inhibition of ERK or STAT3, or SOCS3 knockdown.
• Phosphorylation levels were assessed using ELISA and immunohistology.
• Protein interactions (SOCS3-p120 Ras-GAP) were analyzed by co-immunoprecipitation and Western blot.
• MMP2 mRNA expression was quantified via real-time PCR.

Main Results:

• IL-6 treatment induced ERK1/2 phosphorylation but not STAT3 activation (p-Tyr705), despite increased Ser727 phosphorylation.
• Inhibition of STAT3 enhanced IL-6R-induced ERK phosphorylation, and vice versa.
• SOCS3 and p120 Ras-GAP co-immunoprecipitated upon IL-6 stimulation.
• SOCS3 knockdown permitted STAT3 phosphorylation following IL-6 treatment.
• Inhibition of IL-6R signaling affected IL-6-modulated MMP-2 mRNA expression.

Conclusions:

• SOCS3 interaction with p120 Ras-Gap is critical for directing IL-6R signaling towards ERK activation in dermal fibroblasts.
• This mechanism contributes to the selective signaling elicited by the IL-6R system.
• Findings provide a basis for potential manipulation of IL-6R function.