HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Blair, L. A. Articles by Corbett, J. A. Search for Related Content PubMed PubMed Citation Articles by Blair, L. A. Articles by Corbett, J. A. Social Bookmarking                What's this?

Double-Stranded RNA—Dependent Protein Kinase Is Not Required for Double-Stranded RNA—Induced Nitric Oxide Synthase Expression or Nuclear Factor-B Activation by Islets

From the Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri.

Address correspondence and reprint requests to Dr. John A. Corbett, St. Louis University School of Medicine, Department of Biochemistry and Molecular Biology, 1402 South Grand Blvd., St. Louis, MO 63104. E-mail: corbettj{at}slu.edu .

Environmental factors, such as viral infection, have been implicated in the destruction of ß-cells during the development of autoimmune diabetes. Double-stranded RNA (dsRNA), produced during viral replication, is an active component of a viral infection that stimulates antiviral responses in infected cells. Previous studies have shown that treatment of rat islets with dsRNA in combination with -interferon (IFN-) results in a nitric oxide-dependent inhibition of glucose-stimulated insulin secretion. This study examines the role of nuclear factor-B (NF-B) and the dsRNA-dependent protein kinase (PKR) in dsRNA + IFN--induced nitric oxide synthase (iNOS) expression and nitric oxide production by rat, mouse, and human islets. Treatment of rat and human islets with dsRNA in the form of polyinosinic-polycytidylic acid (poly IC) and IFN- resulted in iNOS expression and nitric oxide production. Inhibitors of NF-B activation—the proteasome inhibitor MG-132 and the antioxidant pyrrolidinedithiocarbamate (PDTC)—prevented poly IC + IFN--induced iNOS expression and nitric oxide production. Incubation of rat islets for 3 h or human islets for 2 h with poly IC alone or poly IC + IFN- resulted in NF-B nuclear translocation and degradation of the NF-B inhibitor protein, IB, events that are prevented by MG-132. PKR has been shown to participate in dsRNA-induced NF-B activation in a number of cell types, including mouse embryonic fibroblasts. However, poly IC stimulated NF-B nuclear translocation and IB degradation to similar levels in islets isolated from mice devoid of PKR (PKR^-/-) and wild-type mice (PKR^+/+). Furthermore, the genetic absence of PKR did not affect dsRNA + IFN--induced iNOS expression, nitric oxide production, or the inhibitory actions of these agents on glucose-stimulated insulin secretion. These results suggest that 1) NF-B activation is required for dsRNA + IFN--induced iNOS expression, 2) PKR is not required for either dsRNA-induced NF-B activation or dsRNA + IFN--induced iNOS expression by islets, and 3) PKR is not required for dsRNA + IFN--induced inhibition of glucose-stimulated insulin secretion by islets.

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				S. A. Steer, J. M. Moran, B. S. Christmann, L. B. Maggi Jr, and J. A. Corbett Role of MAPK in the Regulation of Double-Stranded RNA- and Encephalomyocarditis Virus-Induced Cyclooxygenase-2 Expression by Macrophages. J. Immunol., September 1, 2006; 177(5): 3413 - 3420. [Abstract] [Full Text] [PDF]

				M. Flodstrom-Tullberg, M. Hultcrantz, A. Stotland, A. Maday, D. Tsai, C. Fine, B. Williams, R. Silverman, and N. Sarvetnick RNase L and Double-Stranded RNA-Dependent Protein Kinase Exert Complementary Roles in Islet Cell Defense during Coxsackievirus Infection J. Immunol., February 1, 2005; 174(3): 1171 - 1177. [Abstract] [Full Text] [PDF]

				L. Wen, J. Peng, Z. Li, and F. S. Wong The Effect of Innate Immunity on Autoimmune Diabetes and the Expression of Toll-Like Receptors on Pancreatic Islets J. Immunol., March 1, 2004; 172(5): 3173 - 3180. [Abstract] [Full Text] [PDF]

				L. B. Maggi Jr., J. M. Moran, R. M. L. Buller, and J. A. Corbett ERK Activation Is Required for Double-stranded RNA- and Virus-induced Interleukin-1 Expression by Macrophages J. Biol. Chem., May 2, 2003; 278(19): 16683 - 16689. [Abstract] [Full Text] [PDF]

				S. A. Steer, J. M. Moran, L. B. Maggi Jr., R. M. L. Buller, H. Perlman, and J. A. Corbett Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection J. Immunol., January 15, 2003; 170(2): 1070 - 1076. [Abstract] [Full Text] [PDF]

				D. Liu, A. K. Cardozo, M. I. Darville, and D. L. Eizirik Double-Stranded RNA Cooperates with Interferon-{gamma} and IL-1{beta} to Induce Both Chemokine Expression and Nuclear Factor-{kappa}B-Dependent Apoptosis in Pancreatic {beta}-Cells: Potential Mechanisms for Viral-Induced Insulitis and {beta}-Cell Death in Type 1 Diabetes Mellitus Endocrinology, April 1, 2002; 143(4): 1225 - 1234. [Abstract] [Full Text] [PDF]

				L. A. Blair, L. B. Maggi Jr., A. L. Scarim, and J. A. Corbett Role of Interferon Regulatory Factor-1 in Double-stranded RNA-induced iNOS Expression by Mouse Islets J. Biol. Chem., January 4, 2002; 277(1): 359 - 365. [Abstract] [Full Text]

				A. L. Scarim, M. Arnush, L. A. Blair, J. Concepcion, M. R. Heitmeier, D. Scheuner, R. J. Kaufman, J. Ryerse, R. M. Buller, and J. A. Corbett Mechanisms of {beta}-Cell Death in Response to Double-Stranded (ds) RNA and Interferon-{{gamma}} : dsRNA-Dependent Protein Kinase Apoptosis and Nitric Oxide-Dependent Necrosis Am. J. Pathol., July 1, 2001; 159(1): 273 - 283. [Abstract] [Full Text] [PDF]