Differential Role of IFN-γ-Inducible Protein 10 kDa in a Cockroach Antigen-Induced Model of Allergic Airway Hyperreactivity: Systemic Versus Local Effects

Abstract

The ability of IFN-γ to antagonize established Th2 type allergic responses is well documented. To investigate the role of IFN-γ-inducible protein 10 kDa (IP10) in the allergic response, we chose to investigate the effect of IP10 neutralization on an established Th2 response. Systemic neutralization of IP10 at the time of allergen challenge increased airway hyperreactivity as well as airway eosinophil accumulation. Interestingly, IFN-γ levels were markedly reduced in both the lung and peripheral lymph node following IP10 neutralization. Furthermore, the number of CXCR3+CD4+ T cells was decreased in the peripheral lymph node following neutralization of IP10. Introduction of exogenous IP10 into the airway at the time of allergen challenge also dramatically increased eosinophil accumulation in the airway. Protein levels of IL-4, IL-5, and IL-13 were significantly increased in the lung following exogenous airway administration of IP10 with allergen. Interestingly, airway hyperreactivity was significantly decreased at early time points following concurrent IP10 and allergen challenge but rebounded at 24 and 48 h post allergen challenge. Although IP10 may initially be acting locally to dampen the allergic response, its ability to recruit eosinophils may ultimately supersede any immunomodulatory effect it may have in an established allergic response. These results suggest that while systemic levels of IP10 are beneficial in controlling the allergic response, possibly by regulating cellular trafficking in the lymph node, local administration of exogenous IP10 into an established allergic response may be detrimental.

Regulation of Cockroach Antigen-Induced Allergic Airway Hyperreactivity by the CXCR3 Ligand CXCL9

“…Eosinophils highly express CCR3 and chemotax to the CCR3 ligand CCL11 (59 -62). Eosinophils have also been shown to express CXCR3 (34,63). We have shown that although CXCL10 is a sufficient chemotactic stimulus for eosinophils, CXCL9 inhibits eosinophil chemotaxis in vitro.…”

“…However, CXCL10 transgenic mice displayed increased eosinophil accumulation, airway hyperreactivity, and IL-4 levels after OVA challenge (48). Similarly, introduction of exogenous CXCL10 into an allergic lung increased Th2-type cytokines, airway hyperreactivity, and eosinophil accumulation after allergen challenge (34). Thus, the role of CXCL10 is complex and probably depends on the location and timing of production.…”

“…Cytokine protein concentrations in these lung homogenates and BAL supernatants were quantified using basic sandwich ELISAs as previously described (34).…”

“…Overexpression of CXCL10 during sensitization to OVA has been shown to decrease levels of Th2-type cytokines and eosinophil accumulation in the airway after OVA challenge (33). CXCL10 has also been demonstrated to enhance pulmonary eosinophil accumulation and increase pulmonary levels of Th2 type cytokines after cockroach allergen challenge (34).…”

Interferon-Inducible Protein 10, but Not Monokine Induced by Gamma Interferon, Promotes Protective Type 1 Immunity in MurineKlebsiella pneumoniaePneumonia

“…The recombinant murine IP-10 and MIG antibodies and biotinylated anti-murine IP-10 and MIG antibodies used in the enzyme-linked immunosorbent assays (ELISAs) were purchased from R&D Systems (Minneapolis, MN). Polyclonal rabbit anti-murine IP-10 antibody was generated as previously described and then purified prior to use (34). Monoclonal anti-murine MIG antibody (clone 2A6.9.9) used for in vivo neutralization studies was generated as previously described (41).…”