The inflammasome activates caspase-1 and the release of interleukin-1β (IL-1β) and IL-18, and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) ...in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA, and AIM2 expression is reduced in several types of cancer, but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that
Aim2
-deficient mice had greater tumor load than
Asc
-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in
Aim2
−/−
/
Apc
Min/+
than in APC
Min/+
mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1β and were primarily mediated by a non–bone marrow source of AIM2. In resting cells, AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK), a PI3K-related family member that promotes Akt phosphorylation, whereas loss of AIM2 promoted DNA-PK–mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models, while an Akt inhibitor reduced tumor load in
Aim2
−/−
mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
While it is well established that CD8 super(+) T cells generated in the absence of CD4 super(+) T cells mediate defective recall responses, the mechanism by which CD4 super(+) T cells confer help in ...the generation of CD8 super(+) T-cell responses remains poorly understood. To determine whether CD4 super(+) T-cell-derived IL-21 is an important regulator of CD8 super(+) T-cell responses in help-dependent and -independent viral infections, we examined these responses in the IL-21R alpha super(-/-) mouse model. We show that IL-21 has a role in primary CD8 super(+) T-cell responses and in recall CD8 super(+) T-cell responses in help-dependent viral infections. This effect is due to a direct action of IL-21 in enhancing the proliferation of virus-specific CD8 super(+) T cells and reducing their TRAIL expression. These findings indicate that IL-21 is an important mediator of CD4 super(+) T-cell help to CD8 super(+) T cells.
NLRC5-dependent activation of the inflammasome Davis, Beckley K.; Roberts, Reid A.; Huang, Max T. ...
The Journal of immunology (1950),
12/2010, Letnik:
186, Številka:
3
Journal Article
Recenzirano
The nucleotide-binding domain (NBD) leucine rich repeat (LRR) containing proteins, NLRs, are intracellular sensors of PAMPs and DAMPs. A subgroup of NLRs can form inflammasome complexes, which ...facilitate the maturation of pro-caspase-1 to caspase-1, leading to IL-1β and IL-18 cleavage and secretion.
NLRC5
is predominantly expressed in hematopoetic cells and has not been studied for inflammasome function. RNAi-mediated knockdown of NLRC5 nearly eliminated caspase-1, IL-1β and IL-18 processing in response to bacterial infection, PAMPs and DAMPs. This was confirmed in primary human monocytic cells. NLRC5 together with procaspase-1, pro-IL-1β and the inflammasome adaptor, ASC, reconstituted inflammasome activity which showed cooperativity with NLPR3. The range of pathogens that activate NLRC5 inflammasome overlaps with those that activate NLRP3. Furthermore, NLRC5 biochemically associates with NLRP3 in an NBD-dependent but LRR-inhibitory fashion. These results invoke a model where NLRC5 interacts with NLRP3 to cooperatively activate the inflammasome.
IL-21, a member of the common gamma -chain family of cytokines, has pleiotropic effects on T, B, and NK cells. We found that IL-21 and the prototype common gamma -chain cytokine IL-2 can stimulate ...proliferation and cytokine secretion by Ag-specific rhesus monkey CD8 super(+) T cells. However, unique among the members of this family of cytokines, we found that IL-21 drives these cells to apoptosis by down-regulation of Bcl-2. These findings suggest that IL-21 may play an important role in the contraction of CD8 super(+) T cell responses.
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