A novel p40-independent function of IL-12p35 is required for progression and maintenance of herpes stromal keratitis.
PURPOSE. Interleukin (IL)-12p40 can couple with IL-12p35 or p19 chains to form the molecules IL-12p70 and IL-23, respectively, which promote T(H)1 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(+) T(H)1 cell-dependent corneal inflammation, is demonstrated. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.
Frank
Gregory M
GM
Graduate Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Divito
Sherrie J
SJ
Maker
Dawn M
DM
Xu
Min
M
Hendricks
Robert L
RL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003319:Corneal Stroma / Q000821:virology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D018259:Herpesvirus 1, Human / Q000502:physiology; D053765:Interleukin-12 Subunit p35 / Q000502:physiology*; D053762:Interleukin-12 Subunit p40 / Q000502:physiology*; D016849:Keratitis, Herpetic / Q000276:immunology / Q000821:virology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
D016207:Cytokines; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40