RESUMEN
Colitis-associated colorectal cancer (CAC) is the most serious complication of inflammatory bowel disease (IBD). Excessive complement activation has been shown to be involved in the pathogenesis of IBD. However, its role in the development of CAC is largely unknown. Here, using a CAC model induced by combined administration of azoxymethane (AOM) and dextran sulfate sodium (DSS), we demonstrated that complement activation was required for CAC pathogenesis. Deficiency in key components of complement (e.g., C3, C5, or C5a receptor) rendered tumor repression in mice subjected to AOM/DSS. Mechanistic investigation revealed that complement ablation dramatically reduced proinflammatory cytokine interleukin (IL)-1ß levels in the colonic tissues that was mainly produced by infiltrating neutrophils. IL-1ß promoted colon carcinogenesis by eliciting IL-17 response in intestinal myeloid cells. Furthermore, complement-activation product C5a represented a potent inducer for IL-1ß in neutrophil, accounting for downregulation of IL-1ß levels in the employed complement-deficient mice. Overall, our study proposes a protumorigenic role of complement in inflammation-related colorectal cancer and that the therapeutic strategies targeting complement may be beneficial for the treatment of CAC in clinic.
Asunto(s)
Carcinogénesis/inmunología , Colitis/patología , Neoplasias Colorrectales/patología , Activación de Complemento/fisiología , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Animales , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Colitis/inmunología , Colitis/metabolismo , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Progresión de la Enfermedad , Citometría de Flujo , Immunoblotting , Inmunohistoquímica , Mucosa Intestinal/metabolismo , Intestinos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunologíaRESUMEN
Neutrophil infiltration is a key event in chronic intestinal inflammation and associated colorectal cancer, but how these cells support cancer development is poorly understood. In this study, using a mouse model of colitis-associated cancer (CAC), we have demonstrated that infiltrated neutrophils produce large amounts of interleukin-1 (IL)-1ß that is critical for the development of CAC. Depletion of neutrophil or blockade of IL-1ß activity significantly reduced mucosal damage and tumor formation. This protumorigenic function of IL-1ß was mainly attributed to increased IL-6 secretion by intestine-resident mononuclear phagocytes (MPs). Furthermore, commensal flora-derived lipopolysaccharide (LPS) was identified to trigger IL-1ß expression in neutrophils. Importantly, accumulation of IL-1ß-expressing neutrophils was seen in lesions of patients suffering from ulceratic CAC and these infiltrated neutrophils induced IL-6 production by intestinal MPs in an IL-1ß-dependent manner. Overall, these findings reveal that in CAC milieu, infiltrating neutrophils secrete IL-1ß that promotes tumorigenesis by inducing IL-6 production by intestinal MPs.
Asunto(s)
Carcinogénesis/inmunología , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/inmunología , Neoplasias del Colon/etiología , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Infiltración Neutrófila/inmunología , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Reacción en Cadena de la PolimerasaRESUMEN
In this model study, we simulated the initial airway reopening event in a rigid tube model. The air-liquid interface during airway reopening was assumed to be a simple axisymmetric meniscus similar to that of a two-phase flow in a rigid tube (radius R), where the applied pressures and the meniscus velocities were measured experimentally for fluids of different viscosities and surface tensions (gamma). Bulk flow contribution was deducted from the applied pressure to obtain the pressure accounting for interfacial movement (P*(int)). A semi-empirical formula for the interface was generated by dimensional analysis. The dimensionless interfacial pressure (P(int) = P*(int),R/gamma) was found to approach 2 for sufficiently small velocities, consistent with Bretherton's theoretical prediction. This formula also resembles that previously obtained in collapsible tubes simulating airways. The result suggests that the critical pressures required to reopen a collapsible airway and a non-collapsible one with the same radius are similar in magnitude (approximately 2 - 3gamma/R). However, in a collapsible airway, no significant bulk flow of lining fluids would develop while the interface proceeds, leading to a much smaller overall pressure for further reopening. Airway wall collapsibility thus could play a crucial role in maintaining proper ventilation through rapid reopening of the airway.