3,6-Anhydro-L-galactose suppresses mouse lymphocyte proliferation by attenuating JAK-STAT growth factor signal transduction and G1-S cell cycle progression 4658

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Abstract Description Immunosuppressive drugs have been pivotal in the prevention of allograft rejection and treatment of autoimmune and allergic diseases, and are used individually or in combination to optimize the management of inappropriate immune responses. However, the persistence of several side effects underscores the urgent need to develop new, target-specific immunosuppressive agents. The agarose-degradation product 3,6-anhydro-L-galactose (L-AHG) has been found to inhibit the proliferation of immobilized anti-CD3/anti-CD28-activated T cells and immobilized anti-CD40 + soluble anti-IgM + interleukin (IL)-4-activated B cells, with IC50 values of 55.5 and 34.0 μg/mL, respectively. This inhibition impacted the G1-S traverse in the cell cycle without influencing CD69 expression and p27Kip1 down-regulation, which are markers of the exit from G0 into G1 in activated lymphocytes. L-AHG impeded cyclin-dependent kinases (CDKs)-driven retinoblastoma phosphorylation, which is necessary for the G1-S traverse, by reducing the activating phosphorylation of CDKs (CDK4, CDK2, and CDK1) and lowering cyclin D3, cyclin A2 and cyclin B1 levels. Furthermore, L-AHG diminished the production of growth factors, including IL-2 in activated T cells and IL-6 in activated B cells. L-AHG inhibited JAK1, affecting STAT1 and STAT3 signaling. These results demonstrate that L-AHG may serve as a novel immunosuppressant by impairing JAK-STAT growth factor signaling and G1-S cell cycle progression in T and B lymphocytes. Funding Sources This work was supported by a grant (2022) from the Kyungpook National University, and a grant from AT-31 BIO Inc., Daegu 41566, South Korea. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

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