We have biologically characterized two new members of the IL-17 cytokine family: IL-17F and IL-25. In contrast to conventional in vitro screening approaches, we have characterized the activity of these new molecules by direct in vivo analysis and have compared their function to that of other IL-17 family members. Intranasal administration of adenovirus expressing IL-17, IL-17C, or IL-17F resulted in bronchoalveolar lavage neutrophilia and inflammatory gene expression in the lung. In contrast, intranasal administration of IL-25-expressing adenovirus or IL-25 protein resulted in the production of IL-4, IL-5, IL-13, and eotaxin mRNA in the lung and marked eosinophilia in the bronchoalveolar lavage and lung tissue. Mice given intranasal IL-25 also developed epithelial cell hyperplasia, increased mucus secretion, and airway hyperreactivity. IL-25 gene expression was detected following Aspergillus and Nippostrongylus infection in the lung and gut, respectively. IL-25-induced eosinophilia required IL-5 and IL-13, but not IL-4 or T cells. Following IL-25 administration, the IL-5+ staining cells were CD45R/B220+, Thy-1+/−, but were NK1.1-, Ly-6G(GR-1)-, CD4-, CD3-, and c-kit-negative. γ-common knockout mice did not develop eosinophilia in response to IL-25, nor were IL-5+ cells detected. These findings suggest the existence of a previously unrecognized cell population that may initiate Th2-like responses by responding to IL-25 in vivo. Further, these data demonstrate the heterogeneity of function within the IL-17 cytokine family and suggest that IL-25 may be an important mediator of allergic disease via production of IL-4, IL-5, IL-13, and eotaxin.
To investigate the role of interleukin-5 (IL-5) on airway hyperreactivity and pulmonary inflammation in nonhuman primate airways, the effect of a neutralizing monoclonal antibody to murine IL-5 (TRFK-5) was investigated in a cynomolgus monkey model of allergic asthma. Anesthetized Ascaris-sensitive monkeys underwent bronchoalveolar lavage (BAL) to assess the granulocyte content of this fluid before and 24 h after aerosolized Ascaris suum extract inhalation. Airway reactivity was assessed by the concentration of inhaled histamine required to produce a 40% reduction in dynamic lung compliance (Cdyn40). Exposure to A. suum extract produced an increase in airway reactivity (Cdyn40 = 0.065 +/- 0.024% before Ascaris; Cdyn40 = 0.014 +/- 0.004% after Ascaris) and an inflammatory reaction in the airways characterized by an increase in BAL eosinophils (0.05 +/- 0.03 x 10(3) cells/ml before Ascaris; 176 +/- 76 x 10(3) cells/ml after Ascaris) and neutrophils (3 +/- 1 x 10(3) cells/ml before Ascaris; 406 +/- 211 x 10(3) cells/ml after Ascaris). In contrast, only small nonsignificant changes in airway reactivity and granulocyte influx into the BAL occurred after aerosolized saline as a sham challenge. When the monkeys were treated 1 h before Ascaris challenge with the TRFK-5 antibody (0.3 mg/kg, intravenously), there was no increase in airway reactivity after Ascaris challenge (Cdyn40 = 0.032 +/- 0.016% before Ascaris; Cdyn40 = 0.217 +/- 0.196% after Ascaris) and there were only small increases in the number of eosinophils and neutrophils in the BAL after Ascaris challenge. The inhibition of this pulmonary eosinophilia and bronchial hyperresponsiveness by TRFK-5 was seen for up to 3 mo after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
It has been hypothesized that the destruction of lung tissue observed in smokers with chronic obstructive pulmonary disease and emphysema is mediated by neutrophils recruited to the lungs by smoke exposure. This study investigated the role of the chemokine receptor CXCR2 in mediating neutrophilic inflammation in the lungs of mice acutely exposed to cigarette smoke. Exposure to dilute mainstream cigarette smoke for 1 h, twice per day for 3 days, induced acute inflammation in the lungs of C57BL/6 mice, with increased neutrophils and the neutrophil chemotactic CXC chemokines macrophage inflammatory protein (MIP)-2 and KC. Treatment with SCH-N, an orally active small molecule inhibitor of CXCR2, reduced the influx of neutrophils into the bronchoalveolar lavage (BAL) fluid. Histological changes were seen, with drug treatment reducing perivascular inflammation and the number of tissue neutrophils. β-Glucuronidase activity was reduced in the BAL fluid of mice treated with SCH-N, indicating that the reduction in neutrophils was associated with a reduction in tissue damaging enzymes. Interestingly, whereas MIP-2 and KC were significantly elevated in the BAL fluid of smoke exposed mice, they were further elevated in mice exposed to smoke and treated with drug. The increase in MIP-2 and KC with drug treatment may be due to the decrease in lung neutrophils that either are not present to bind these chemokines or fail to provide a feedback signal to other cells producing these chemokines. Overall, these results demonstrate that inhibiting CXCR2 reduces neutrophilic inflammation and associated lung tissue damage due to acute cigarette smoke exposure.
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