The kinase inhibitory region of SOCS-1 is sufficient to inhibit T-helper 17 and other immune functions in experimental allergic encephalomyelitis

Abstract

Suppressors of cytokine signaling (SOCS) negatively regulate the immune response, primarily by interfering with the JAK/STAT pathway. We have developed a small peptide corresponding to the kinase inhibitory region (KIR) sequence of SOCS-1, SOCS1-KIR, which inhibits kinase activity by binding to the activation loop of tyrosine kinases such as JAK2 and TYK2. Treatment of SJL/J mice with SOCS1-KIR beginning 12 days post-immunization with myelin basic protein (MBP) resulted in minimal symptoms of EAE, while most control treated mice developed paraplegia. SOCS1-KIR treatment suppressed interleukin-17A (IL-17A) production by MBP-specific lymphocytes, as well as MBP-induced lymphocyte proliferation. When treated with IL-23, a key cytokine in the terminal differentiation of IL-17-producing cells, MBP-sensitized cells produced IL-17A and IFNγ; SOCS1-KIR was able to inhibit the production of these cytokines. SOCS1-KIR also blocked IL-23 and IL-17A activation of STAT3. There is a deficiency of SOCS-1 and SOCS-3 mRNA expression in CD4 + T cells that infiltrate the CNS, reflecting a deficiency in regulation. Consistent with therapeutic efficacy, SOCS1-KIR reversed the cellular infiltration of the CNS that is associated with EAE. We have shown here that a SOCS-1 like effect can be obtained with a small functional region of the SOCS-1 protein that is easily produced.

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…Specifically, treatment with SOCS1 mimetic peptides, analogous to KIR, or a tyrosine kinase inhibitor peptide (Tkip) protects mice from developing murine encephalomyelitis and from the increased inflammatory response observed in keratinocytes stimulated with LPS (52)(53)(54). These results illustrate the potential for developing strategies based on SOCS1 in therapeutics targeting the pathogenesis of inflammatory disease.…”

“…Structurally, SOCS1 is composed of three main domains: KIR, SH2, and SOCS box (6,11). Although here we studied the role of KIR domain in the pathogenesis of sepsis, the role of the other SOCS1 domains remains to be determined (53,54). We focused our present efforts on deciphering the role of the KIR domain because it has been implicated in the pathogenesis of other inflammatory diseases (6).…”

Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

“…A therapeutic SOCS1 KIR mimetic peptide has shown great promise in preventing the development of multiple sclerosis in a mouse experimental autoimmune encephalomyelitis model and even ameliorates clinical symptoms of lupus in a rodent model (97). From our studies presented here, a therapeutic SOCS1 mimetic peptide may have a profound effect on IL-4-initiated IRS-2 signaling and M2 macrophage polarization and the severity of allergic disease by interrupting signaling pathways downstream of IL-4.…”

Suppressor of Cytokine Signaling 1–Derived Peptide Inhibits Janus Kinase/Signal Transducers and Activators of Transcription Pathway and Improves Inflammation and Atherosclerosis in Diabetic Mice

“…38,39 Similarly, peptides containing SOCS1 inhibitory sequence suppress STAT activation by Th1 and Th17 cytokines in leukocytes, splenocytes, and keratinocytes. [40][41][42] To date, the in vivo effects of SOCS1 mimetic sequences have investigated in mouse models of multiple sclerosis, 38,41 peripheral nerve injury, 43 and viral infection 39 but not in cardiovascular and metabolic diseases. Our study provides first evidence that a small peptide corresponding to the SOCS1 kinase inhibitory region has atheroprotective effects.…”