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Impaired T Cell Protein Kinase C Activation Decreases ERK Pathway Signaling in Idiopathic and Hydralazine-Induced Lupus¹

Gabriela Gorelik^*, Jing Yuan Fang, Ailing Wu^*, Amr H. Sawalha and Bruce Richardson^2,*,

^* Department of Medicine, University of Michigan, and Ann Arbor Veterans Affairs Medical Center, Ann Arbor, MI 48109; Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine, Renji Hospital, Shanghai, China; and U.S. Department of Veterans Affairs Medical Center, Department of Medicine, University of Oklahoma Health Sciences Center, and Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104

T cells from patients with lupus or treated with the lupus-inducing drug hydralazine have defective ERK phosphorylation. The reason for the impaired signal transduction is unknown but important to elucidate, because decreased T cell ERK pathway signaling causes a lupus-like disease in animal models by decreasing DNA methyltransferase expression, leading to DNA hypomethylation and overexpression of methylation-sensitive genes with subsequent autoreactivity and autoimmunity. We therefore analyzed the PMA stimulated ERK pathway phosphorylation cascade in CD4⁺ T cells from patients with lupus and in hydralazine-treated cells. The defect in these cells localized to protein kinase C (PKC). Pharmacologic inhibition of PKC or transfection with a dominant negative PKC mutant caused demethylation of the TNFSF7 (CD70) promoter and CD70 overexpression similar to lupus and hydralazine-treated T cells. These results suggest that defective T cell PKC activation may contribute to the development of idiopathic and hydralazine-induced lupus through effects on T cell DNA methylation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Grants AR42525, AG25877, and ES15214 and a Merit grant from the Department of Veterans Affairs.

² Address correspondence and reprint requests to Dr. Bruce Richardson, 3007 Biomedical Science Research Building, Department of Medicine, University of Michigan, Ann Arbor, MI 48109-2200. E-mail address: brichard{at}umich.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; PKC, protein kinase C; DNMT1, DNA (cytosine-5-) methyltransferase 1; RA, rheumatoid arthritis; RBD, Ras binding domain.