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Journal of Virology, June 2009, p. 5978-5986, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.00315-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Interleukin-12 (IL-12), but Not IL-23, Deficiency Ameliorates Viral Encephalitis without Affecting Viral Control{triangledown}

Parul Kapil,1,2 Roscoe Atkinson,3 Chandran Ramakrishna,1,{dagger} Daniel J. Cua,4 Cornelia C. Bergmann,1 and Stephen A. Stohlman1*

Department of Neurosciences NC30, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44195,1 Department of Biological, Geological and Environmental Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, Ohio 44115,2 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033,3 Shering-Plough Biopharma, 901 California Ave., Palo Alto, California 943044

Received 12 February 2009/ Accepted 24 March 2009

The relative contributions of interleukin-12 (IL-12) and IL-23 to viral pathogenesis have not been extensively studied. IL-12p40 mRNA rapidly increases after neurotropic coronavirus infection. Infection of mice defective in both IL-12 and IL-23 (p40–/–), in IL-12 alone (p35–/–), and in IL-23 alone (p19–/–) revealed that the symptoms of coronavirus-induced encephalitis are regulated by IL-12. IL-17-producing cells never exceeded background levels, supporting a redundant role of IL-23 in pathogenesis. Viral control, tropism, and demyelination were all similar in p35–/–, p19–/–, and wild-type mice. Reduced morbidity in infected IL-12 deficient mice was also not associated with altered recruitment or composition of inflammatory cells. However, gamma interferon (IFN-{gamma}) levels and virus-specific IFN-{gamma}-secreting CD4 and CD8 T cells were all reduced in the central nervous systems (CNS) of infected p35–/– mice. Transcription of the proinflammatory cytokines IL-1β and IL-6, but not tumor necrosis factor, were initially reduced in infected p35–/– mice but increased to wild-type levels during peak inflammation. Furthermore, although transforming growth factor β mRNA was not affected, IL-10 was increased in the CNS in the absence of IL-12. These data suggest that IL-12 does not contribute to antiviral function within the CNS but enhances morbidity associated with viral encephalitis by increasing the ratio of IFN-{gamma} to protective IL-10.

* Corresponding author. Mailing address: Department of Neuroscience NC30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Phone: (216) 445-9796. Fax: (216) 444-7927. E-mail: stohlms2{at}ccf.org

{triangledown} Published ahead of print on 1 April 2009.

{dagger} Present address: Department of Virology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010.

Journal of Virology, June 2009, p. 5978-5986, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.00315-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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