RESUMO
Pellino-1 has recently been identified as a regulator of interleukin-1 (IL-1) signaling, but its roles in regulation of responses of human cells to human pathogens are unknown. We investigated the potential roles of Pellino-1 in the airways. We show for the first time that Pellino-1 regulates responses to a human pathogen, rhinovirus minor group serotype 1B (RV-1B). Knockdown of Pellino-1 by small interfering RNA (siRNA) was associated with impaired production of innate immune cytokines such as CXCL8 from human primary bronchial epithelial cells in response to RV-1B, without impairment in production of antiviral interferons (IFN), and without loss of control of viral replication. Pellino-1 actions were likely to be independent of interleukin-1 receptor-associated kinase-1 (IRAK-1) regulation, since Pellino-1 knockdown in primary epithelial cells did not alter responses to IL-1 but did inhibit responses to poly(I·C), a Toll-like receptor 3 (TLR3) activator that does not signal via IRAK-1 to engender a response. These data indicate that Pellino-1 represents a novel target that regulates responses of human airways to human viral pathogens, independently of IRAK signaling. Neutralization of Pellino-1 may therefore provide opportunities to inhibit potentially harmful neutrophilic inflammation of the airways induced by respiratory viruses, without loss of control of the underlying viral infection.
Assuntos
Células Epiteliais/imunologia , Proteínas Nucleares/imunologia , Infecções por Picornaviridae/imunologia , Rhinovirus/fisiologia , Ubiquitina-Proteína Ligases/imunologia , Adolescente , Adulto , Idoso , Linhagem Celular , Células Cultivadas , Células Epiteliais/virologia , Feminino , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Infecções por Picornaviridae/genética , Infecções por Picornaviridae/virologia , Rhinovirus/genética , Rhinovirus/imunologia , Transdução de Sinais , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Ubiquitina-Proteína Ligases/genética , Adulto JovemRESUMO
Rhinoviral infection is an important trigger of acute inflammatory exacerbations in patients with underlying airway disease. We have previously established that interleukin-1ß (IL-1ß) is central in the communication between epithelial cells and monocytes during the initiation of inflammation. In this study we explored the roles of IL-1ß and its signaling pathways in the responses of airway cells to rhinovirus-1B (RV-1B) and further determined how responses to RV-1B were modified in a model of bacterial coinfection. Our results revealed that IL-1ß dramatically potentiated RV-1B-induced proinflammatory responses, and while monocytes did not directly amplify responses to RV-1B alone, they played an important role in the responses observed with our coinfection model. MyD88 is the essential signaling adapter for IL-1ß and most Toll-like receptors. To examine the role of MyD88 in more detail, we created stable MyD88 knockdown epithelial cells using short hairpin RNA (shRNA) targeted to MyD88. We determined that IL-1ß/MyD88 plays a role in regulating RV-1B replication and the inflammatory response to viral infection of airway cells. These results identify central roles for IL-1ß and its signaling pathways in the production of CXCL8, a potent neutrophil chemoattractant, in viral infection. Thus, IL-1ß is a viable target for controlling the neutrophilia that is often found in inflammatory airway disease and is exacerbated by viral infection of the airways.
