Involvement of mitogen-activated protein kinases in the signal transduction pathway of bone marrow-derived macrophage activation in response to in vitro treatment with thymosin alpha 1.

Thymosin alpha 1 (Talpha1), a 28-amino acid, acidic thymic peptide, is a promising natural biological response modifier (BRM), which augments and regulates the immune network and is thought to be immunostimulatory also. Recently, we have reported the ability of Talpha1 to activate macrophages to tumoricidal state. In the present investigation, the activation of the p42/44 MAP kinase (MAPK)/c-Jun NH2 terminal kinase (JNK) pathway in response to in vitro treatment with Talpha1 in murine bone marrow-derived macrophages (BMDMs) has been demonstrated. The activation and expression of phospho-p42/44 MAPK was dose as well as time dependent with maximum expression occurring at 5-15 min following stimulation with 100 ng/ml of Talpha1. The expression of phospho-p42/44 MAPK was inhibited by the MAPK inhibitor, PD98059, pertussis toxin (PTX), tyrosine kinase inhibitor-genistein and P13K inhibitor-wortmannin. Talpha1-induced BMDM tumoricidal functions like the production of NO and TNF-alpha, the key mediator molecules of macrophage cytotoxicity, were also inhibited by the MAPK inhibitor, PD98059, in a dose-dependent manner. These observations suggest that p42/44 MAPK activation is one of the essential signaling events triggered by Talpha1 and may be responsible for the in vitro activation of BMDMs.