When a cytokine storm starts (such as IL6, IL10, and IFN-gamma) after infections, toxins, or injury, the body produces SOCS3 to try to dampen this response – hence the name suppressor of cytokine signaling. SOCS3 stands for Suppressor Of Cytokine Signaling 3. SOCS3 subsequently causes leptin resistance, obesity, and glucose intolerance (R, R2).

SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS3 is involved in negative regulation of cytokines that signal through the JAK/STAT pathway. Inhibits cytokine signal transduction by binding to tyrosine kinase receptors including gp130, LIF, erythropoietin, insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its kinase activity. Suppresses fetal liver erythropoiesis. Regulates onset and maintenance of allergic responses mediated by T-helper type 2 cells. Regulates IL-6 signaling in vivo (By similarity). Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Seems to recognize IL6ST.

Introduction to SOCS3

Suppressor Of Cytokine Signaling 3 or SOCS3. When a cytokine storm starts (such as IL6, IL10, and IFN-gamma) after infections, toxins, or injury, the body produces SOCS3 to try to dampen this response – hence the name suppressor of cytokine signaling.

SOCS3 causes subsequent leptin resistance, obesity, and glucose intolerance (R, R2). In some immune cells such as dendritic cells (found in the gut and other places), SOCS3 causes them to be less tolerant and more reactive to foreign proteins (R).

In macrophages and dendritic cells, SOCS3 increases TNF, IL-12, and MHC-II/HLA expression, which are all inflammatory. SOCS3 also lowers IL-10 and Tregs, which are anti-inflammatory (R). All of these changes are bad.

SOCS3, Obesity and Th2 Dominance

SOCS3 skews the immune system to a Th2 dominant profile (by blocking IL-12 induced STAT4) (R). In my observations, Th2 dominant people are more likely to be overweight. SOCS3, in part, explains this link, since SOCS3 causes Th2 dominance and also leptin resistance, which results in obesity. Science has confirmed my observation that obese people are more likely to be Th2 dominant and obesity is an important risk factor in the development of asthma (and other Th2 conditions) (R). Leptin's effect on weight loss depends on cellular signals that it activates, including STAT3. SOCS3 is able to block this signal and stop the effects that leptin has on weight loss. Mechanism: Leptin-> STAT3->Weight loss. The problem is that STAT3 also causes Th1/Th17 related inflammation.  So while you will be thinner, you will be at increased risk for certain kinds of inflammation. SOCS3 blocks STAT3, which reduces Th1/Th17 inflammation, but increases leptin resistance and Th2 dominance.

Higher SOCS3 (The BAD):

• Causes leptin resistance (R)
• Causes Insulin resistance (R) (via decreasing IRS-1 (R)).
• Causes obesity (R).
• Is found in pregnancy, which can increase risks for developing obesity and type II diabetes during pregnancy (R) and may be a contributing cause of preterm labor (R). An increase in SOCS3 levels during pregnancy allows for the pregnant mother to increase food consumption in order to provide nutrients to her infant.
• Reduces the activity of pancreatic cells, which could cause type 2 diabetes by lowering insulin secretion (R).

Higher SOCS3 (The GOOD):

• Suppresses cancer growth by decreasing Th17 cytokines (R).
• Suppresses breast cancer (R) as well as many other cancers (R, R2), by decreasing STAT3 (R).
• Slows liver tumor growth (R).
• May prevent liver cell death, liver cancer, and liver failure (R).
• May prevent heart contractile dysfunctions and arrhythmias (R).

Do You Have High SOCS3?

You are more likely to have higher SOCS3 if you:

• Are Th2 dominant
• Gain weight easily
• Have chronic inflammation from mycobacteria, TGF-beta1, and MMP9.

     From UniProt: There is some evidence that SOCS3 may be a susceptibility gene for atopic dermatitis linked to 17q25. SOCS3 messenger RNA is significantly more highly expressed in skin from patients with atopic dermatitis than in skin from healthy controls. Furthermore, a genetic association between atopic dermatitis and a haplotype in the SOCS3 gene has been found in two independent groups of patients.

     From NCBI Gene: This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma. The protein encoded by this gene can bind to JAK2 kinase, and inhibit the activity of JAK2 kinase. Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development. [provided by RefSeq, Jul 2008] From UniProt: SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS3 is involved in negative regulation of cytokines that signal through the JAK/STAT pathway. Inhibits cytokine signal transduction by binding to tyrosine kinase receptors including gp130, LIF, erythropoietin, insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its kinase activity. Suppresses fetal liver erythropoiesis. Regulates onset and maintenance of allergic responses mediated by T-helper type 2 cells. Regulates IL-6 signaling in vivo (By similarity). Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Seems to recognize IL6ST.

What Inhibits SOCS3

Supplements

• Butyrate -Calcium/Magnesium (R) – reverses a high fat diet-induced increase in SOCS3 in animals.
• Ecklonia cava (R)
• Bilberry (by preventing STAT3 activation) (R)
• Resveratrol effectively suppresses SOCS3 gene expression (R)
• Lycopene (R)
• PQQ (R)
• Probiotics (R)
• Chromium (nano-sized Cr tri-picolinate) (R)

SIRT1

SIRT1 decreases SOCS3 in the hypothalamus and in turn decreases leptin resistance (R). So if you have good levels/high activity of SIRT1, you will have lower SOCS3 and lower leptin resistance.

Robust SIRT1 comes from circadian rhythm entrainment. In the SIRT1 post, there are a number of SIRT1 activators, which you can use to inhibit SOCS3.

Resveratrol and Nicotinamide Riboside/Niagen NAD+ are two powerful supplements to increase SIRT1 and its activity.