IL-1α Modulates IFN-γ-Induced Production of CXCL9/MIG during Herpes Simplex Virus Type-1 Corneal Infection

Investigating the modulation of neutrophil production of MIG and IP-10 during the inflammatory response to HSV-1 infection.

An ex vivo model of human corneal infection by HSV-1 was used for this study. This model permits the study of cytokine production by human corneal buttons in the presence, or absence, of gradient purified human neutrophils, under conditions of HSV-1 infection. All experimental samples were stimulated with a baseline concentration of recombinant human IFN-γ at 1 ng/mL. The relative levels of production for 12 pro-inflammatory mediators were screened using a multi-analyte ELISA assay. Neutrophil production of chemokines MIG and IP-10, under conditions of IFN-γ and/or HSV-1 stimulation were measured by quantitative ELISA. Lastly, antibody neutralization (goat IgG anti-human IL-1α, 2 µg/mL) of de novo production of IL-1α by corneal tissue was performed to investigated the effect on MIG and IP-10 production in the ex vivo model for HSV-1 infection.

Four of the 12 pro-inflammatory mediators screened (IL-8, IL-6, IL-1α and IL-1β) demonstrated elevated levels of production during corneal cell infection with HSV-1 and communication with neutrophils. Neutrophils were demonstrated to produce significant levels of both MIG and IP-10 under conditions of IFN-γ stimulation, and production of MIG was further upregulated by co-stimulation with IFN-γ and HSV-1. Neutralization of de novo IL-1α production in the model resulted in increased production of the chemokine production MIG but had no observable effect on IP-10 production.

Our data provide evidence demonstrating the potential for expression patterns of MIG and IP-10 to be modulated by IL-1α, during the inflammatory response to HSV-1 corneal infection. Both corneal cells and neutrophils contribute to the production of T cell recruiting chemokines. However, IL-1α has the potential to upregulate MIG production by corneal cells while down-regulating MIG production by neutrophils.