Functional IL-10 Deficiency in the Lung of Cystic Fibrosis (cftr−/−) and IL-10 Knockout Mice Causes Increased Expression and Function of B7 Costimulatory Molecules on Alveolar Macrophages

Abstract

Alveolar macrophages are poor APCs that only minimally express B7 costimulatory molecules. Because our previous data suggest that bronchial epithelial cells constitutively secrete IL-10, and IL-10 inhibits B7 expression in vitro, we hypothesized that this IL-10 is responsible for suppressing B7 expression on macrophages that enter the airways. Furthermore, because we have shown that cystic fibrosis (CF) lungs are deficient in IL-10, we hypothesized that bronchoalveolar macrophages (BALMs) from cystic fibrosis transmembrane conductance regulator (CFTR)−/− as well as IL-10−/− mice might express increased B7. Immunofluorescence for B7 was positive on BALMs from CF patients and CFTR−/− and IL-10−/− mice, but was negative on controls. FACS showed that 63.9% of BALMs from IL-10−/− mice were B7-1 positive, as were 67.4% of BALMs from CFTR−/− mice, whereas <7% of BALMs from wild-type controls were positive. Using BALMs to costimulate splenic T cells with anti-CD3 as a mitogen showed 9202 ± 2107 cpm [3H]thymidine incorporation for BALMs from IL-10−/− mice and 4082 ± 1036 cpm for BALMs from CFTR−/− mice, but <200 cpm with BALMs from either type of +/+ mouse. Treatment of CFTR−/− mice with recombinant mouse IL-10 reduced the B7 expression and costimulatory activity of the BALMs. These data suggest that the IL-10 secreted in the healthy lung may be responsible for the absence of B7 and poor costimulatory activity of BALMs and that reductions of pulmonary IL-10 in CF may enhance B7 expression and local immune responses.

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

“…Inflammatory cytokines, which are known to be altered in the BALF of CF mice (5), affect the activation of DCs (45). The decreased concentrations of IL-10 in the CF lung have been shown to lead to an increase in the expression of CD80 and CD86 (14), contrary to the phenotype seen in CF lung DCs. One factor abundantly present in CF airway fluid that could inhibit the maturation of pulmonary DCs is NE.…”

“…Proliferation in response to Pseudomonas aeruginosa antigens is impaired in CF lymphocytes (13). Moreover, the reduced IL-10 that is characteristic of the CF lung milieu increases the cleavage of costimulatory molecule B7 on human macrophages (14).…”

IL-10 delivery by AAV5 vector attenuates inflammation in mice with pseudomonas pneumonia

“…A study was also carried out with intraperitoneal injection of rIL-10 to CFTR knockout mice resulting in decreased T-cell costimulatory molecule B7 and poor co-stimulatory activity of bronchoalveolar macrophages. 30 As bronchoalveolar macrophages from patients with CF have been shown to actively produce the proinflammatory cytokines which are elevated in CF BAL, 3,10 treatment with IL-10 may suppress the synthesis of these proinflammatory cytokines and alter T-cell responses. Further supporting our results with AAV5.Cb-mIL10, Sawa et al 29 administered rIL-10 intraperitoneally before or after acute P. aeruginosa infection in Balb/c mice, finding decreased lung injury and mortality and a decreased inflammatory response.…”

“…[21][22][23][24] IL-10T mice repeatedly exposed to mucoid P. aeruginosa have higher mortality rates and more severe lung pathology when compared with C57BL/6 controls similarly infected; 25 in addition, IL-10T mice have a prolonged inflammatory response to acute P. aeruginosa challenge. 26 Research shows that treatment with IL-10 reduces neutrophil and leukocyte recruitment, decreases proinflammatory cytokine production, and causes an increase in weight loss and tissue injury in the airways of sensitized animals following antigen exposure or P. aeruginosa challenge, 19,21,[27][28][29][30] supporting the use of IL-10 in ameliorating inflammation.…”

TGFβ-dependent gene expression profile during maturation of dendritic cells

“…Hence, activation of DC is continuously attenuated by immunosuppressive cytokines 3 such as transforming growth factorb (TGFb). [4][5][6] TGFb belongs to a well-defined multi-potent cytokine family involved in many pathophysiological events. 7 Three isoforms (TGFb1, TGFb2 and TGFb3) that bear overlapping activities are expressed in mammals.…”