期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 308, 期 2, 页码 G139-G150出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00234.2014
关键词
colitis-associated cancer; inflammasome; inflammatory bowel disease; nucleotide-binding domain and leucine-rich repeat containing protein; noncanonical inflammasome
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [K01DK092355]
Nucleotide-binding domain and leucine-rich repeat containing protein inflammasome formation plays an essential role in modulating immune system homeostasis in the gut. Recently, a caspase-11 noncanonical inflammasome has been characterized and appears to modulate many biological functions that were previously considered to be solely dependent on caspase-1 and the canonical inflammasome. To better elucidate the function of this noncanonical inflammasome during inflammatory bowel disease, experimental colitis was induced in wild-type and Casp11(-/-) mice utilizing dextran sulfate sodium ( DSS). Here, we report that caspase-11 attenuates acute experimental colitis pathogenesis. Casp11(-/-) mice showed significantly increased morbidity and colon inflammation following DSS exposure. Subsequent cytokine analysis revealed that IL-1 beta and IL-18 levels in the colon were significantly reduced in the Casp11(-/-) mice compared with the wild-type animals. Additional mechanistic studies utilizing IL-1 beta and IL-18 reconstitution revealed that Casp11(-/-) hypersensitivity was associated with the loss of both of these cytokines. Bone marrow reconstitution experiments further revealed that caspase-11 gene expression and function in both hematopoietic-and nonhematopoietic-derived cells contribute to disease attenuation. Interestingly, unlike caspase-1, caspase-11 does not appear to influence relapsing remitting disease progression or the development of colitis-associated tumorigenesis. Together, these data identify caspase-11 as a critical factor protecting the host during acute DSS-induced colonic injury and inflammation but not during chronic inflammation and tumorigenesis.
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