SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis

Abstract

RA is an autoimmune disease characterized by sustained imbalance between pro-and antiinflammatory immune mechanisms. The SOCS proteins are negative regulators of cytokine signaling, but to date there has been little information on their function in disease. The generation of Socs3 -/Dvav mice, which lack SOCS-3 in the hematopoietic and endothelial cell compartment, allowed us to explore the role of endogenous SOCS-3 during acute inflammatory arthritis. Joint inflammation in Socs3 -/Dvav mice was particularly severe and was characterized by increased numbers of neutrophils in the inflamed synovium, bone marrow, peripheral blood, and spleen. These features were most likely due to increased production of and enhanced responsiveness to G-CSF and IL-6 during arthritis in these mice. Local osteoclast generation and bone destruction were also dramatically increased in the absence of SOCS-3, as was macrophage activation. Finally, SOCS-3 was found to negatively regulate CD4 + T lymphocyte activation, including production of the pleiotropic cytokine IL-17. The absence of SOCS-3 therefore had dramatic effects in this disease model, with a broader impact on cellular responses than SOCS-1 deficiency. These findings provide direct in vivo evidence that endogenous SOCS-3 is a critical negative regulator of multiple cell types orchestrating inflammatory joint disease.

Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression

“…These results suggest a critical role for AhR in the regulation of inflammatory responses. Similar to the phenotype of AhR LKO mice, deletion of the Socs3 gene increases infiltration of neutrophils and macrophages and heightens inflammation (40,(51)(52)(53). Given the facts that (i) expression of AhR and Socs3 is induced by HFD (Fig.…”

Neuronal nicotinic alpha7 receptors modulate inflammatory cytokine production in the skin following ultraviolet radiation

“…In this study we find that coincident with UVB exposure, SOCS3 protein expression decreases which is consistent with an increase in the inflammatory cytokines IL-1β and IL-6. While SOCS3 regulation of IL-6 is well-known to require elements of the JAK-STAT pathway, the mechanism through which SOCS3 regulates IL-1β is less clearly resolved (Frobose et al, 2006;Karlsen et al, 2004;Wong et al, 2006). The SOCS3 effect appears to be robust since de Jonge et al (de Jonge et al, 2005) have reported that vagal anti-inflammatory effects in macrophages through nAChRα7 involve activation of Jak2-STAT3.…”

Distinct regulation of interleukin‐17 in human T helper lymphocytes

“…Both IL-6 and IL-23 activate the transcription factor STAT-3, which directly binds to the IL-17 promoter to regulate IL-17 expression (32). Conversely, suppressor of cytokine signaling 3 negatively regulates Th17 differentiation by inhibiting STAT-3 phosphorylation (32,33). In addition to STAT-3, retinoic acidrelated orphan receptor ␥t (ROR␥t) is an important transcription factor for initiation of Th17 differentiation (34).…”