The Role of Calmodulin Kinase II (CaMKII) in the Phosphorylation of the Serine 727 Residue of Signal Transducer and Activator of Transcription 1 (STAT1) and its Therapeutic Significance
Sanker, Christopher R.
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Although multiple sclerosis (MS) cannot be classified as a true autoimmune disease, it is characterized by the immune-mediated attack and destruction of oligodendrocytes (the myelin forming cells of the central nervous system (CNS))n and the myelin sheaths surrounding CNS neurons. Subnormal immune responses to interferon-alpha (IFN-𝛼.) and beta (IFN-𝛽), two molecules necessary for regulating antiviral activity have been observed in peripheral blood mononuclear cells (MNCs) of MS patients. This suggests an underlying defect in type I IFN signaling in MS. In addition, it has been shown that MS progression is ameliorated by type I interferon therapy. Combined, these findings implicate IFN's in the etiology of MS. It is suggested that they correct anomalous immune regulation via an unknown mechanism. In an effort to elucidate the mechanism of action of IFN-𝛽 therapy, this study investigated three events: a) Tyr 701 phosphorylation of STATl, an event directly responsible for the activation of this pathway, b) Ser 727 phosphorylation of STATl, which is responsible for enhancing transcription of IFN induced genes, and c) candidate kinases likely to be responsible for P-Ser-STATl formation. Western blot analysis of peripheral mononuclear cells (MNCs) from patients receiving IFN treatment indicated that the ability of IFN therapies A vonex (Biogen), Betaseron (Berlex), and Rebif (Serono) to induce P-Ser-STATl formation varies significantly with time and dose, implicating P-Ser-STATl as a possible point of regulation in type I interferon therapy. Furthermore in vitro experiments in which MNCs were stimulated with IFN-𝛽 and exposed to various kinase inhibitors indicated that the MEK Kinase, Calmodulin Kinase II may be responsible for the Ser 727 phosphorylation of STATI. These findings suggest novel insight into the molecular mechanism of action underlying IFN-𝛽 therapy.