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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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Selective induction of epithelial IL-12 p40 expression in asthmatic subjects. In A, endobronchial biopsies from normal control, asthmatic, and chronic bronchitis subjects were immunostained with control nonimmune IgG or with anti–IL-12 p40 or p35 Ab as described in the legend to Fig. 3. Bar, 20 μm. Representative photomicrographs of biopsies from seven control, seven asthmatic, and eight chronic bronchitis subjects are shown. In B, endobronchial biopsy sections from conditions in A underwent quantification of epithelial IL-12 p40 immunostaining relative to a subepithelial reference set at a value of 100. For each condition, values represent mean ± SEM for each cohort, and a significant increase from immunostaining with control nonimmune IgG is indicated by (*).
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Figure 9: Selective induction of epithelial IL-12 p40 expression in asthmatic subjects. In A, endobronchial biopsies from normal control, asthmatic, and chronic bronchitis subjects were immunostained with control nonimmune IgG or with anti–IL-12 p40 or p35 Ab as described in the legend to Fig. 3. Bar, 20 μm. Representative photomicrographs of biopsies from seven control, seven asthmatic, and eight chronic bronchitis subjects are shown. In B, endobronchial biopsy sections from conditions in A underwent quantification of epithelial IL-12 p40 immunostaining relative to a subepithelial reference set at a value of 100. For each condition, values represent mean ± SEM for each cohort, and a significant increase from immunostaining with control nonimmune IgG is indicated by (*).

Mentions: The results in mice suggest that overexpression of IL-12 p40 by the airway epithelium may lead to airway inflammation. As noted above, we have suggested that abnormal programming of epithelial immune response genes may serve as a basis for airway inflammation due to asthma 79. Accordingly, we next determined the level of IL-12 p40 and p35 expression in endobronchial biopsies and IL-12 and IL-12 p40 levels in BAL fluid obtained from normal versus asthma or chronic bronchitis subjects (characterized in Table ). In endobronchial biopsies, we found that airway epithelial cell IL-12 p40 expression was present in each of seven asthmatic but none of seven normal or eight chronic bronchitis subjects, whereas IL-12 p35 expression was constitutively expressed in airway epithelial, parenchymal, and inflammatory cells from all groups of subjects (Fig. 9). In addition, we found that increased epithelial IL-12 p40 expression in asthmatic subjects resulted in increased BAL fluid IL-12 p40 (but not IL-12 p70) concentrations that was unaltered by the concomitant administration of inhaled or systemic glucocorticoids (Fig. 10A and Fig. B). Additional experiments using a glucocorticoid withdrawal protocol to compare six asthmatic subjects to themselves with and without glucocorticoid treatment confirmed the lack of correlation between treatment status and IL-12 p40 levels in BAL fluid (20.5 ± 8.5 pg/ml and 31.4 ± 8.0 pg/ml with and without treatment, respectively; P > 0.05). Further analysis of BAL fluid samples indicated that IL-12 p40 appeared to be expressed predominantly as the homodimer (although background in concentrated BAL fluid is necessarily increased) and to correlate with macrophage accumulation (Fig. 10C and Fig. D). The asthmatic BAL fluid IL-12 p40/p70 ratio was elevated relative to normal subjects at a level (mean ratio of 221 ± 86) similar to the one found in viral bronchitis. Taken together, this data indicated that airway epithelial IL-12 p40 overexpression (particularly as the homodimer) may similarly contribute to airway inflammation in asthmatic subjects as it does during viral infection.


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)

Selective induction of epithelial IL-12 p40 expression in asthmatic subjects. In A, endobronchial biopsies from normal control, asthmatic, and chronic bronchitis subjects were immunostained with control nonimmune IgG or with anti–IL-12 p40 or p35 Ab as described in the legend to Fig. 3. Bar, 20 μm. Representative photomicrographs of biopsies from seven control, seven asthmatic, and eight chronic bronchitis subjects are shown. In B, endobronchial biopsy sections from conditions in A underwent quantification of epithelial IL-12 p40 immunostaining relative to a subepithelial reference set at a value of 100. For each condition, values represent mean ± SEM for each cohort, and a significant increase from immunostaining with control nonimmune IgG is indicated by (*).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195918&req=5

Figure 9: Selective induction of epithelial IL-12 p40 expression in asthmatic subjects. In A, endobronchial biopsies from normal control, asthmatic, and chronic bronchitis subjects were immunostained with control nonimmune IgG or with anti–IL-12 p40 or p35 Ab as described in the legend to Fig. 3. Bar, 20 μm. Representative photomicrographs of biopsies from seven control, seven asthmatic, and eight chronic bronchitis subjects are shown. In B, endobronchial biopsy sections from conditions in A underwent quantification of epithelial IL-12 p40 immunostaining relative to a subepithelial reference set at a value of 100. For each condition, values represent mean ± SEM for each cohort, and a significant increase from immunostaining with control nonimmune IgG is indicated by (*).
Mentions: The results in mice suggest that overexpression of IL-12 p40 by the airway epithelium may lead to airway inflammation. As noted above, we have suggested that abnormal programming of epithelial immune response genes may serve as a basis for airway inflammation due to asthma 79. Accordingly, we next determined the level of IL-12 p40 and p35 expression in endobronchial biopsies and IL-12 and IL-12 p40 levels in BAL fluid obtained from normal versus asthma or chronic bronchitis subjects (characterized in Table ). In endobronchial biopsies, we found that airway epithelial cell IL-12 p40 expression was present in each of seven asthmatic but none of seven normal or eight chronic bronchitis subjects, whereas IL-12 p35 expression was constitutively expressed in airway epithelial, parenchymal, and inflammatory cells from all groups of subjects (Fig. 9). In addition, we found that increased epithelial IL-12 p40 expression in asthmatic subjects resulted in increased BAL fluid IL-12 p40 (but not IL-12 p70) concentrations that was unaltered by the concomitant administration of inhaled or systemic glucocorticoids (Fig. 10A and Fig. B). Additional experiments using a glucocorticoid withdrawal protocol to compare six asthmatic subjects to themselves with and without glucocorticoid treatment confirmed the lack of correlation between treatment status and IL-12 p40 levels in BAL fluid (20.5 ± 8.5 pg/ml and 31.4 ± 8.0 pg/ml with and without treatment, respectively; P > 0.05). Further analysis of BAL fluid samples indicated that IL-12 p40 appeared to be expressed predominantly as the homodimer (although background in concentrated BAL fluid is necessarily increased) and to correlate with macrophage accumulation (Fig. 10C and Fig. D). The asthmatic BAL fluid IL-12 p40/p70 ratio was elevated relative to normal subjects at a level (mean ratio of 221 ± 86) similar to the one found in viral bronchitis. Taken together, this data indicated that airway epithelial IL-12 p40 overexpression (particularly as the homodimer) may similarly contribute to airway inflammation in asthmatic subjects as it does during viral infection.

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