Proinflammatory functions of IL-2 in herpes simplex virus corneal infection.
Herpes simplex virus type 1 infection of corneas can lead to blinding inflammation in the corneal stroma, which is referred to clinically as herpes stromal keratitis. In our mouse model of this prevalent human disease, a heavy polymorphonuclear neutrophil (PMN) infiltration of the infected cornea leads to progressive tissue destruction. This inflammatory process can be abrogated by in vivo depletion of CD4 T lymphocytes and by neutralization of the cytokines IL-2 and IFN-gamma. The goal of this study was to define the mechanisms by which IL-2 mediates the corneal inflammation. Systemic neutralization of IL-2 after the onset of corneal disease resulted in a rapid regression of inflammation and complete resolution in 50% of the treated mice. The disease remission was associated with loss of IFN-gamma expression in the cornea, as determined by immunohistochemistry, and a significant reduction of IFN-gamma mRNA, as measured by a semiquantitative reverse transcription-PCR analysis. Within 48 h after anti-IL-2 mAb administration, the PMN chemotactic gradient in the infected corneas was abolished, and those PMN that were already present in the central cornea exhibited clear signs of apoptotic cell death. Our results demonstrate that IL-2 mediates corneal inflammation by 1) regulating local IFN-gamma production in an autocrine or a paracrine fashion, 2) establishing a PMN chemotactic gradient, and 3) maintaining PMN viability in the cornea. These results suggest that IL-2 might be targeted for therapeutic intervention in this blinding disease.
Tang
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Q
Department of Microbiology and Immunology, University of Illinois, Chicago 60612, USA.
Chen
W
W
Hendricks
R L
RL
D000818:Animals; D002470:Cell Survival; D002634:Chemotaxis, Leukocyte; D005260:Female; D018259:Herpesvirus 1, Human / Q000472:pathogenicity*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000502:physiology*; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D009504:Neutrophils / Q000276:immunology
D007376:Interleukin-2; D007371:Interferon-gamma