Expression of the Th1 Chemokine IFN-γ-Inducible Protein 10 in the Airway Alters Mucosal Allergic Sensitization in Mice

Allergic airway disease is characterized by a robust lymphocytic infiltrate, elaboration of Th2-type inflammatory mediators, pulmonary eosinophil accumulation, and airway hyperreactivity. The CXCR3 ligands, CXCL9 (monokine induced by IFN-γ) and CXCL10 (IFN-inducible protein, 10 kDa), are IFN-γ-inducible, Th1-type chemokines. As CXCL10 has been previously shown to participate in the modulation of allergic inflammation, we were interested in investigating the possible role that CXCL9 may play in this inflammatory response. Expression of CXCL9 was primarily identified in airway epithelial cells by immunohistochemical staining. Airway neutralization of CXCL9 at the time of allergen challenge significantly increased airway hyperreactivity, airway eosinophil accumulation, and IL-4 levels in the bronchoalveolar lavage while significantly decreasing airway levels of IL-12. In contrast, introduction of exogenous CXCL9 into the airway at the time of allergen challenge dramatically reduced airway hyper-reactivity and eosinophil accumulation. Moreover, pulmonary levels of IL-4 were significantly reduced, whereas levels of IL-12 were significantly increased, with exogenous CXCL9 treatment. In lymphocytes restimulated with CXCL9 and allergen in vitro, CXCL9 down-regulated IL-4 expression and up-regulated IFN-γ expression, suggesting that CXCL9 is able to direct activated lymphocytes toward a Th1-type phenotype. Additionally, CXCL9 was shown to inhibit CC chemokine ligand 11-induced eosinophil chemotaxis in in vitro assays. Taken together, our results demonstrate that the CXCR3 ligand CXCL9 is involved in regulation of the allergic response in the lung by regulation of lymphocyte activation and eosinophil recruitment.

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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

Thomas

Kunkel

Lukacs

2004

“…Whether CXCL9 and CXCL10 enhance or dampen allergic inflammation may depend on the location and timing of their production. For example, in a mouse model, targeted overexpression of CXCL10 to the lung inhibited the development of Ag-induced airway eosinophilia (41). The authors suggested that this was most likely due to recruitment of Th1-type cells that shifted the balance away from a Th2 response.…”

Section: Discussionmentioning

confidence: 99%

Generation of Th1 and Th2 Chemokines by Human Eosinophils: Evidence for a Critical Role of TNF-α

Liu

Bates

Jarjour

et al. 2007

116

102

Emerging evidence suggests a role for eosinophils in immune regulation of T cells. Thus, we sought to determine whether human eosinophils may exert their effect via differential generation of Th1 and Th2 chemokines depending on cytokines in their microenvironment and, if so, to establish the conditions under which these chemokines are produced. Eosinophils cultured with TNF-α plus IL-4 had increased mRNA expression and protein secretion of the Th2-type chemokines, CCL17 (thymus and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine). Conversely, the Th1-type chemokines, CXCL9 (monokine induced by IFN-γ) and CXCL10 (IFN-γ-inducible protein-10), were expressed after stimulation with TNF-α plus IFN-γ. Addition of TNF-α appeared to be essential for IFN-γ-induced release of Th1-type chemokines and significantly enhanced IL-4-induced Th2-type chemokines. Inhibition of NF-κB completely blocked the production of both Th1 and Th2 chemokines. Activation of NF-κB, STAT6, and STAT1 was induced in eosinophils by TNF-α, IL-4, and IFN-γ, respectively. However, there was no evidence for enhancement of these signaling events when eosinophils were stimulated with the combination of TNF-α plus IL-4 or TNF-α plus IFN-γ. Thus, independently activated signaling cascades appear to lead to activation of NF-κB, STAT1, and STAT6, which may then cooperate at the promoter level to increase gene transcription. Our data demonstrate that TNF-α is a vital component for eosinophil chemokine generation and that, depending on the cytokines present in their microenvironment, eosinophils can promote either a Th2 or a Th1 immune response, supporting an immunoregulatory role for eosinophils.

“…The overexpression of (27,29). In addition, the observation that introduction of exogenous IFN-␥ into the airway can initially down-regulate the Th2-induced response may suggest that IP10 can have an immunomodulatory role during allergic responses (23,26).…”

Section: Discussionmentioning

confidence: 99%

“…However, it is unclear whether IFN-␥ acts directly or indirectly by altering local and/or systemic inflammatory immune responses. Recently, it has been shown that overexpression of IP10 during sensitization to OVA decreased levels of IL-4 and eosinophil accumulation in the airway following OVA challenge (29). To further investigate the role of IP10 in the allergic response, the effect of neutralization of IP10 at the time of allergen challenge was investigated in these studies.…”

mentioning

confidence: 99%

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

Thomas

Kunkel

Lukacs

2002

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.