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Interleukin 12 p40 production by barrier epithelial cells during airway inflammation.

Walter MJ, Kajiwara N, Karanja P, Castro M, Holtzman MJ - J. Exp. Med. (2001)

Bottom Line: To better determine how this epithelial system operates in vivo, we analyzed its behavior in mouse models that allow for in vitro versus in vivo comparison and genetic modification.Induction of IL-12 p40 was even further increased in IL-12 p35-deficient mice, and in this case, was associated with increased mortality and epithelial macrophage accumulation.Taken together, these results suggest a novel role for epithelial-derived IL-12 p40 in modifying the level of airway inflammation during mucosal defense and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

ABSTRACT
Human airway epithelial cells appear specially programmed for expression of immune response genes implicated in immunity and inflammation. To better determine how this epithelial system operates in vivo, we analyzed its behavior in mouse models that allow for in vitro versus in vivo comparison and genetic modification. Initial comparisons indicated that tumor necrosis factor alpha induction of epithelial intercellular adhesion molecule 1 required sequential induction of interleukin (IL)-12 (p70) and interferon gamma, and unexpectedly localized IL-12 production to airway epithelial cells. Epithelial IL-12 was also inducible during paramyxoviral bronchitis, but in this case, initial IL-12 p70 expression was followed by 75-fold greater expression of IL-12 p40 (as monomer and homodimer). Induction of IL-12 p40 was even further increased in IL-12 p35-deficient mice, and in this case, was associated with increased mortality and epithelial macrophage accumulation. The results placed epithelial cell overgeneration of IL-12 p40 as a key intermediate for virus-inducible inflammation and a candidate for epithelial immune response genes that are abnormally programmed in inflammatory disease. This possibility was further supported when we observed IL-12 p40 overexpression selectively in airway epithelial cells in subjects with asthma and concomitant increases in airway levels of IL-12 p40 (as homodimer) and airway macrophages. Taken together, these results suggest a novel role for epithelial-derived IL-12 p40 in modifying the level of airway inflammation during mucosal defense and disease.

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TNF-α induction of IL-12 expression drives downstream production of IFN-γ. Wild-type (WT), IL-12 p35 (−/−), and IFN-γ (−/−) C57BL/6J mice were treated with vehicle alone (PBS) or TNF-α as described in the legend to Fig. 1, followed 12 h later by BAL. The BAL fluid was concentrated 10-fold and used for duplicate measurements of IL-12 and IFN-γ levels by ELISA. Values represent mean ± SEM (n = 4). Levels of IL-12 were undetectable in IL-12 p35 (−/−) mice. A significant increase from PBS-treated wild-type cohort (by ANOVA) is indicated by (*).
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Figure 2: TNF-α induction of IL-12 expression drives downstream production of IFN-γ. Wild-type (WT), IL-12 p35 (−/−), and IFN-γ (−/−) C57BL/6J mice were treated with vehicle alone (PBS) or TNF-α as described in the legend to Fig. 1, followed 12 h later by BAL. The BAL fluid was concentrated 10-fold and used for duplicate measurements of IL-12 and IFN-γ levels by ELISA. Values represent mean ± SEM (n = 4). Levels of IL-12 were undetectable in IL-12 p35 (−/−) mice. A significant increase from PBS-treated wild-type cohort (by ANOVA) is indicated by (*).

Mentions: In other systems, especially Th1 cell development, it appears that IFN-γ production may depend on stimulation by macrophage-derived IL-12 2930. Although TNF-α–driven IL-12 production leading to IFN-γ generation has not been clearly ordered in vivo, we reasoned that this sequence might lead to epithelial ICAM-1 expression in the present model. This possibility was first supported by the finding that TNF-α induction of epithelial ICAM-1 was blocked in mice rendered deficient in IL-12 production by disruption of the IL-12 p35 gene (Fig. 1b and Fig. c). To next define whether TNF-α induction of IL-12 release was upstream of IFN-γ production, we determined levels of IL-12 and IFN-γ in wild-type versus IL-12 p35–deficient mice. We found that TNF-α–driven induction of IL-12 release proceeded as expected in the IFN-γ–deficient mouse, whereas induction of IFN-γ was blocked in the IL-12 p35–deficient mouse (Fig. 2). Taken together, these findings support the possibility that TNF-α initiates a cytokine cascade that includes initial IL-12 followed by IFN-γ release to achieve target gene (in this case, ICAM-1) expression on airway epithelial cells. In these experiments, it appears that induction of IL-12, at least as assessed in BAL fluid, is induced to a level that overcomes any antagonistic action of endogenous IL-12 p40 (Fig. 2).


Interleukin 12 p40 production by barrier epithelial cells during airway inflammation.

Walter MJ, Kajiwara N, Karanja P, Castro M, Holtzman MJ - J. Exp. Med. (2001)

TNF-α induction of IL-12 expression drives downstream production of IFN-γ. Wild-type (WT), IL-12 p35 (−/−), and IFN-γ (−/−) C57BL/6J mice were treated with vehicle alone (PBS) or TNF-α as described in the legend to Fig. 1, followed 12 h later by BAL. The BAL fluid was concentrated 10-fold and used for duplicate measurements of IL-12 and IFN-γ levels by ELISA. Values represent mean ± SEM (n = 4). Levels of IL-12 were undetectable in IL-12 p35 (−/−) mice. A significant increase from PBS-treated wild-type cohort (by ANOVA) is indicated by (*).
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Related In: Results  -  Collection

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Figure 2: TNF-α induction of IL-12 expression drives downstream production of IFN-γ. Wild-type (WT), IL-12 p35 (−/−), and IFN-γ (−/−) C57BL/6J mice were treated with vehicle alone (PBS) or TNF-α as described in the legend to Fig. 1, followed 12 h later by BAL. The BAL fluid was concentrated 10-fold and used for duplicate measurements of IL-12 and IFN-γ levels by ELISA. Values represent mean ± SEM (n = 4). Levels of IL-12 were undetectable in IL-12 p35 (−/−) mice. A significant increase from PBS-treated wild-type cohort (by ANOVA) is indicated by (*).
Mentions: In other systems, especially Th1 cell development, it appears that IFN-γ production may depend on stimulation by macrophage-derived IL-12 2930. Although TNF-α–driven IL-12 production leading to IFN-γ generation has not been clearly ordered in vivo, we reasoned that this sequence might lead to epithelial ICAM-1 expression in the present model. This possibility was first supported by the finding that TNF-α induction of epithelial ICAM-1 was blocked in mice rendered deficient in IL-12 production by disruption of the IL-12 p35 gene (Fig. 1b and Fig. c). To next define whether TNF-α induction of IL-12 release was upstream of IFN-γ production, we determined levels of IL-12 and IFN-γ in wild-type versus IL-12 p35–deficient mice. We found that TNF-α–driven induction of IL-12 release proceeded as expected in the IFN-γ–deficient mouse, whereas induction of IFN-γ was blocked in the IL-12 p35–deficient mouse (Fig. 2). Taken together, these findings support the possibility that TNF-α initiates a cytokine cascade that includes initial IL-12 followed by IFN-γ release to achieve target gene (in this case, ICAM-1) expression on airway epithelial cells. In these experiments, it appears that induction of IL-12, at least as assessed in BAL fluid, is induced to a level that overcomes any antagonistic action of endogenous IL-12 p40 (Fig. 2).

Bottom Line: To better determine how this epithelial system operates in vivo, we analyzed its behavior in mouse models that allow for in vitro versus in vivo comparison and genetic modification.Induction of IL-12 p40 was even further increased in IL-12 p35-deficient mice, and in this case, was associated with increased mortality and epithelial macrophage accumulation.Taken together, these results suggest a novel role for epithelial-derived IL-12 p40 in modifying the level of airway inflammation during mucosal defense and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

ABSTRACT
Human airway epithelial cells appear specially programmed for expression of immune response genes implicated in immunity and inflammation. To better determine how this epithelial system operates in vivo, we analyzed its behavior in mouse models that allow for in vitro versus in vivo comparison and genetic modification. Initial comparisons indicated that tumor necrosis factor alpha induction of epithelial intercellular adhesion molecule 1 required sequential induction of interleukin (IL)-12 (p70) and interferon gamma, and unexpectedly localized IL-12 production to airway epithelial cells. Epithelial IL-12 was also inducible during paramyxoviral bronchitis, but in this case, initial IL-12 p70 expression was followed by 75-fold greater expression of IL-12 p40 (as monomer and homodimer). Induction of IL-12 p40 was even further increased in IL-12 p35-deficient mice, and in this case, was associated with increased mortality and epithelial macrophage accumulation. The results placed epithelial cell overgeneration of IL-12 p40 as a key intermediate for virus-inducible inflammation and a candidate for epithelial immune response genes that are abnormally programmed in inflammatory disease. This possibility was further supported when we observed IL-12 p40 overexpression selectively in airway epithelial cells in subjects with asthma and concomitant increases in airway levels of IL-12 p40 (as homodimer) and airway macrophages. Taken together, these results suggest a novel role for epithelial-derived IL-12 p40 in modifying the level of airway inflammation during mucosal defense and disease.

Show MeSH
Related in: MedlinePlus