RESUMO
Activation of the innate immune system plays a key role in exacerbations of chronic lung disease, yet the potential role of lung fibroblasts in innate immunity and the identity of epithelial danger signals (alarmins) that may contribute to this process are unclear. The objective of the study was to identify lung epithelial-derived alarmins released during endoplasmic reticulum stress (ER stress) and oxidative stress and evaluate their potential to induce innate immune responses in lung fibroblasts. We found that treatment of primary human lung fibroblasts (PHLFs) with conditioned media from damaged lung epithelial cells significantly upregulated interleukin IL-6, IL-8, monocyte chemotactic protein-1, and granulocyte macrophage colony-stimulating factor expression (P<0.05). This effect was reduced with anti-IL-1α or IL-1Ra but not anti-IL-1ß antibody. Costimulation with a Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly I:C), significantly accentuated the IL-1α-induced inflammatory phenotype in PHLFs, and this effect was blocked with inhibitor of nuclear factor kappa-B kinase subunit beta and TGFß-activated kinase-1 inhibitors. Finally, Il1r1-/- and Il1a-/- mice exhibit reduced bronchoalveolar lavage (BAL) neutrophilia and collagen deposition in response to bleomycin treatment. We conclude that IL-1α plays a pivotal role in triggering proinflammatory responses in fibroblasts and this process is accentuated in the presence of double-stranded RNA. This mechanism may be important in the repeated cycles of injury and exacerbation in chronic lung disease.
Assuntos
Células Epiteliais/metabolismo , Fibroblastos/metabolismo , Interleucina-1alfa/metabolismo , Pneumonia/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Células Epiteliais/patologia , Fibroblastos/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1alfa/genética , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Estresse Oxidativo , Fenótipo , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/patologia , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de SinaisRESUMO
Cells of the innate immune system produce cytokines and lipid mediators that strongly influence the outcome of mycobacterial infection. In the case of Mycobacterium tuberculosis, the lung is a critical site for this interaction. Here, we review current information on the role of the major innate cytokine pathways both in controlling initial infection as well as in promoting and maintaining adaptive T-cell responses that mediate host resistance or immunopathology. Understanding this important feature of the host-pathogen interaction can provide major insights into the mechanisms of virulence and can lead to new approaches for immunological intervention in tuberculosis and other mycobacterial diseases.
