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Journal of Virology, September 2001, p. 8008-8015, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8008-8015.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Requirements for the Induction of Interleukin-6 by Herpes Simplex Virus-Infected Leukocytes

Søren R. Paludan*

Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark

Received 2 March 2001/Accepted 29 May 2001

Cytokines play important roles in the clearance of herpes simplex virus (HSV) infections and in virus-induced immunopathology. One cytokine known to contribute to resistance against HSV is interleukin-6 (IL-6). Here we have investigated virus-cell interactions responsible for IL-6 induction by HSV in leukocytes. Both HSV type 1 and type 2 are potent inducers of IL-6, and this phenomenon is augmented in the presence of gamma interferon. The ability to induce IL-6 is dependent on de novo protein synthesis and is sensitive to UV irradiation of the virus. Virus mutants lacking the virion-transactivating protein VP16 or any of the immediate-early proteins ICP0, ICP4, or ICP27 displayed unaltered capacities to induce IL-6. However, wild-type virus was unable to induce IL-6 in a macrophage cell line overexpressing a mutant of double-stranded RNA-activated protein kinase (PKR). This suggests a role for PKR in HSV-induced IL-6 expression. HSV infection led to enhanced binding to the kappa B, CRE, and AP-1 sites of the IL-6 promoter, and inhibitors against NF-kappa B and the p38 kinase strongly reduced accumulation of IL-6 mRNA in infected cells. Moreover, macrophage cell lines expressing dominant negative mutants of Ikappa Balpha and p38 responded to HSV-1 infection with reduced IL-6 expression compared to the control-vector-transfected cell line. The results show that induction of IL-6 by HSV in leukocytes is dependent on PKR and cellular signaling through NF-kappa B and a p38-dependent pathway.

* Mailing address: Department of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark. Phone: (45) 8942 1767. Fax: (45) 8619 6128. E-mail: srp{at}microbiology.au.dk.

Journal of Virology, September 2001, p. 8008-8015, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8008-8015.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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