JAK3 is required for signaling of the type I receptors that use the common gamma chain (γc).Studies suggest Jak3 plays essential roles in immune and nonimmune cell physiology.

A selective Jak3 inhibitor tofacitinib (Xeljanz) approved by the FDA for certain chronic inflammatory conditions demonstrates immunosuppressive activity in rheumatoid arthritis, psoriasis, and organ transplant rejection.

Functional reconstitution of kinase activity by recombinant Jak3 using Jak3-wt or villin/gelsolin-wt as substrate showed that Jak3 autophosphorylation was the rate-limiting step during interactions between Jak3 and cytoskeletal proteins.

Kinetic parameters showed that phosphorylated (P) Jak3 binds to P-villin with a dissociation constant (Kd) of 23 nM and a Hill's coefficient of 3.7.

[10] Sustained damage to the mucosal lining in patients with inflammatory bowel disease (IBD) facilitates translocation of intestinal microbes to submucosal immune cells leading to chronic inflammation.

Higher concentrations of IL-2 decreased the phosphorylation of Jak3, disrupted its interactions with p52ShcA, redistributed Jak3 to the nucleus, and induced apoptosis in IEC.

In differentiated human colonic epithelial cells, Jak3 redistributed to basolateral surfaces and interacted with adherens junction (AJ) protein β-catenin.

Studies in rodent model show that loss of Jak3 results in increased body weight, basal systemic CLGI, compromised glycemic homeostasis, hyperinsulinemia, and early symptoms of liver steatosis.

Mechanistically, it is shown that Jak3 is essential for reduced expression and activation of toll like receptors (TLRs) in murine intestinal mucosa and human intestinal epithelial cells where Jak3 interacted with and activated p85, the regulatory sub-unit of the PI3K, through tyrosine phosphorylation of adapter protein insulin receptor substrate (IRS1).

Overall, Jak3 plays an essential role in promoting mucosal tolerance through suppressed expression and limiting activation of TLRs thereby preventing intestinal and systemic CLGI and associated obesity and MetS.

Functional characterization showed that Jak3 autophosphorylation was the rate-limiting step during Jak3 trans-phosphorylation of β-catenin, where Jak3 directly phosphorylated three tyrosine residues, viz.

These results uncover a mechanism of BCRP-mediated intestinal drug efflux and barrier functions and establish a role for BCRP in preventing CLGI-associated obesity both in humans and in mice.

These studies have wider implications not only in our understanding of physiological and pathophysiological mechanisms of intestinal barrier functions and CLGI associated chronic inflammatory diseases but also in protein-mediated drug-efflux pharmacokinetic and pharmacodynamic characteristics of oral drug formulations.

Previous report suggested that obese humans have a reduced expression of intestinal Jak3 and a deficiency of Jak3 in mice led to predisposition to obesity-associated metabolic syndrome.

Recapitulating these conditions using global (Jak3-KO) and intestinal epithelial cell-specific conditional (IEC-Jak3-KO) mice and using cognitive testing, western analysis, flow cytometry, immunofluorescence microscopy and 16s rRNA sequencing, It was demonstrated that HFD-induced Jak3 deficiency is responsible for cognitive impairments in mice, and these are, in part, specifically due to intestinal epithelial deficiency of Jak3.

It was revealed that Jak3 deficiency leads to gut dysbiosis, compromised TREM-2-functions-mediated activation of microglial cells, increased TLR-4 expression and HIF1-α-mediated inflammation in the brain.

Collectively, these data illustrated how the drivers of obesity promote cognitive impairment and demonstrate the underlying mechanism where HFD-mediated impact on IEC-Jak3 deficiency is responsible for Jak3 deficiency in the brain, reduced microglial TREM2 expression, microglial activation and compromised clearance of Aβ and pTau as the mechanism during obesity-associated cognitive impairments.

Thus, the study not only demonstrated the mechanism of obesity-associated cognitive impairments but also characterize the tissue-specific role of Jak3 in such conditions through mucosal tolerance, gut–brain axis, and regulation of microglial functions.

Once activated, the JAKs create docking sites for the STAT transcription factors by phosphorylation of specific tyrosine residues on the cytokine receptor subunits.

[25] Mutations in the common gamma chain (γc) result in X-linked severe combined immunodeficiency (X-SCID).

[9] The selectivity of a JAK3 inhibitor would also have advantages over the current widely used immunosuppressant drugs, which have abundant targets and diverse side effects.

[9] Tofacitinib also demonstrated immunosuppressive activity in phase I and II clinical trials of rheumatoid arthritis, psoriasis and organ transplant rejection.