Compartmentalized transgene expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse lung enhances allergic airways inflammation

120

121

Airway smooth muscle is actively involved in the inflammatory process in diseases such as chronic obstructive pulmonary disease and asthma by 1) contributing to airway narrowing through hyperplasia and hypertrophy and 2) the release of GM-CSF and G-CSF, which promotes the survival and activation of infiltrating leukocytes. Thus, the identification of novel anti-inflammatory pathways in airway smooth muscle will have important implications for the treatment of inflammatory airway disease. This study identifies such a pathway in the activation of peroxisome proliferator-activated receptors (PPARs). PPAR ligands are known therapeutic agents in the treatment of diabetes; however, their role in human airway disease is unknown. We demonstrate, for the first time, that human airway smooth muscle cells express PPARα and -γ subtypes. Activation of PPARγ by natural and synthetic ligands inhibits serum-induced cell growth more effectively than does the steroid dexamethasone, and induces apoptosis. Moreover, PPARγ activation, like dexamethasone, inhibits the release of GM-CSF. However, PPARγ ligands, but not dexamethasone, similarly inhibits G-CSF release. These results reveal a novel anti-inflammatory pathway in human airway smooth muscle, where PPARγ activation has additional anti-inflammatory effects to those of steroids. Hence, PPAR ligands might act as potential treatments in human respiratory diseases.

Section: Discussionmentioning

confidence: 99%

Activation of Peroxisome Proliferator-Activated Receptors in Human Airway Smooth Muscle Cells Has a Superior Anti-inflammatory Profile to Corticosteroids: Relevance for Chronic Obstructive Pulmonary Disease Therapy

Patel¹,

Belvisi²,

Bishop‐Bailey

et al. 2003

120

121

“…The strategy has advantages over the use of recombinant cytokines, in that the transgene can be expressed in a dose-dependent manner in a specific tissue for a limited period of time. In the present study we used a low dose of the adenoviral construct (26) delivered via the airway to target epithelial cells and to certain extent alveolar macrophages (40), since these cell types are probably major targets for MoPn infection in vivo. We observed that the potent effect of GM-CSF was closely associated with the appearance of increased numbers of DCs, enhanced Agspecific CD4-Th1 immune responses, and increased lung Ag-specific IgA levels and resulted in protection against challenge infection.…”

Section: Discussionmentioning

confidence: 99%

GM-CSF Transgene-Based Adjuvant Allows the Establishment of Protective Mucosal Immunity Following Vaccination with Inactivated Chlamydia trachomatis

Xing

Brunham

2002

Cellular and humoral immune responses induced following murine Chlamydia trachomatis infection confer almost sterile protection against homologous reinfection. On the other hand, immunization with inactivated organism induces little protective immunity in this model system. The underlying mechanism(s) that determines such divergent outcome remains unclear, but elucidating the mechanism will probably be important for chlamydial vaccine development. One of the distinct differences between the two forms of immunization is that chlamydia replication in epithelial cells causes the secretion of a variety of proinflammatory cytokines and chemokines, such as GM-CSF, that may mobilize and mature dendritic cells and thereby enhance the induction of protective immunity. Using a murine model of C. trachomatis mouse pneumonitis lung infection and intrapulmonary adenoviral GM-CSF transfection, we demonstrate that the expression of GM-CSF in the airway compartment significantly enhanced systemic Th1 cellular and local IgA immune responses following immunization with inactivated organisms. Importantly, immunized mice had significantly reduced growth of chlamydia and exhibited less severe pulmonary inflammation following challenge infection. The site of GM-CSF transfection proved important, since mice immunized with inactivated organisms after GM-CSF gene transfer by the i.p. route exhibited little protection against pulmonary challenge, although i.p. immunization generated significant levels of systemic Th1 immune responses. The obvious difference between i.p. and intrapulmonary immunization was the absence of lung IgA responses following i.p. vaccination. In aggregate, the findings demonstrate that the local cytokine environment is critical to the induction of protective immunity following chlamydial vaccination and that GM-CSF may be a useful adjuvant for a chlamydial vaccine.

“…The integrity of Th1-type immune responses seen in IL-12 Ϫ/Ϫ mice is further supported by our finding that the duration of adenoviral-mediated transgene expression in the lung was similar between IL-12 Ϫ/Ϫ and C57BL/6 mice. We have previously shown that adenovirus infects not only airway epithelial cells but also macrophages in the lung (15,26), and it is well known that antiadenoviral cytotoxic responses by CD8 T cells are the major mechanisms underlying the clearance of virus-infected cells and limited virus-mediated transgene expression in these cells (15,27,28). Although we have not conducted a CTL assay to directly address the role of CD8 T cells in our current study, our findings suggest that the clearance of virus-infected cells was not impaired in IL-12 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

IL-12-Independent Th1-Type Immune Responses to Respiratory Viral Infection: Requirement of IL-18 for IFN-γ Release in the Lung But Not for the Differentiation of Viral-Reactive Th1-Type Lymphocytes

Xing

Zganiacz

Jun

et al. 2000

We demonstrated that IL-12 was induced during primary or secondary pulmonary adenoviral infection in wild-type (wt) mice. However, cellular responses were not compromised in the lungs of IL-12−/− mice. The level of IFN-γ in the lung was similar in wt and IL-12−/− mice during pulmonary viral infection. Upon Ag stimulation in vitro, lymphocytes from draining lymph nodes or spleen of infected IL-12−/− mice released large amounts of IFN-γ, but not IL-4, which were comparable to those released by wt lymphocytes. Furthermore, a predominantly IgG2a response to adenoviral infection was unimpaired in IL-12−/− mice. These significant anti-adenoviral Th1-type responses in IL-12−/− mice led to an efficient clearance of virus-infected cells in the lung. Whether IL-18 was involved in IL-12-independent anti-adenoviral immune responses was investigated. Abrogation of endogenous IL-18 by an Ab resulted in diminished IFN-γ release and lymphocytic infiltrate in the lung during adenoviral infection. Nevertheless, the development of lymphocytes of the Th1 phenotype was unimpaired in the absence of both IL-12 and IL-18. In contrast to their intact ability to mount Th1-type responses to viral infection, IL-12−/− mice suffered impaired Th1-type immune responses to pulmonary mycobacterial infection. Our findings suggest that IL-12, although induced, is not required for Th1-type responses to respiratory viral infection, in contrast to mycobacterial infection. IL-18 is required for the optimal release of IFN-γ in the lung during viral infection, but is not required for the generation of virus-reactive Th1-type lymphocytes. Th1 differentiation during respiratory adenoviral infection may involve molecules different from IL-12 or IL-18.