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Gregory M. Frank, Sherrie J. Divito, Dawn M. Maker, Min Xu, Robert L. Hendricks; A Novel p40-Independent Function of IL-12p35 Is Required for Progression and Maintenance of Herpes Stromal Keratitis. Invest. Ophthalmol. Vis. Sci. 2010;51(7):3591-3598. doi: 10.1167/iovs.09-4368.
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Interleukin (IL)-12p40 can couple with IL-12p35 or p19 chains to form the molecules IL-12p70 and IL-23, respectively, which promote TH1 cytokine responses. IL-12p35 can bind to EBI3 to form the anti-inflammatory molecule IL-35, but a proinflammatory function of IL-12p35 independent of IL-12p40 has not been described. Here such a function in a mouse model of herpes stromal keratitis (HSK), a CD4+ TH1 cell–dependent corneal inflammation, is demonstrated.
Corneas of wild-type (WT), IL-12p40−/−, IL-12p35−/−, and IL-12p35−/−p40−/− (double knockout) mice were infected with the RE strain of HSV-1, and HSK was monitored based on corneal opacity, neovascularization, leukocytic infiltrate, and cytokine/chemokine levels.
All mouse strains developed moderate HSK by 11 days after infection (dpi). However, from 11 to 21 dpi, HSK progressed in WT and IL-12p40−/− mice but regressed in IL-12p35−/− and IL-12p35−/−p40−/− mice. HSK regression was characterized by reductions in neutrophils and CD4+ T cells and attenuation of blood vessels, which was associated with reduced levels of the chemokines KC (CXCL3), Mip-2 (CXCL2), and MCP-1 (CCL2) and the angiogenic factor vascular endothelial growth factor.
HSK development does not require IL-12p40 and is thus independent of IL-12p70 and IL-23. However, late HSK progression does require a previously unrecognized IL-12p40–independent, proinflammatory function of IL-12p35.
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