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Beneficial and Detrimental Roles of NLRs in Carcinogenesis.

Janowski AM, Kolb R, Zhang W, Sutterwala FS - Front Immunol (2013)

Bottom Line: One major source of IL-1β and IL-18 secretion is through the activation of inflammasomes.Inflammasomes are multi-protein complexes that upon activation lead to the processing and secretion of IL-1β and IL-18 mediated by the cysteine protease caspase-1.Here we will discuss recent advances in understanding the mechanism by which NLRs regulate carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Inflammation Program, University of Iowa Carver College of Medicine , Iowa City, IA , USA ; Graduate Program in Immunology, University of Iowa Carver College of Medicine , Iowa City, IA , USA.

ABSTRACT
Inflammation plays a critical role in tumorigenesis and can contribute to oncogenic mutations, tumor promotion, and angiogenesis. Tumor-promoting inflammation is driven by many factors including the presence of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. One major source of IL-1β and IL-18 secretion is through the activation of inflammasomes. Inflammasomes are multi-protein complexes that upon activation lead to the processing and secretion of IL-1β and IL-18 mediated by the cysteine protease caspase-1. Several inflammasomes, including NLRP3, NLRC4, and NLRP6, have been implicated in tumorigenesis. However, inflammasomes play divergent roles in different types of cancer reflecting the complexity of inflammation during tumorigenesis. Understanding the role of inflammasome activation during specific stages of tumorigenesis and also during cancer immunotherapy will help identify novel therapeutic targets that could improve treatment strategies for cancer patients. Here we will discuss recent advances in understanding the mechanism by which NLRs regulate carcinogenesis.

No MeSH data available.


Related in: MedlinePlus

(A) Structure of the NLRP3 inflammasome. (B) Cancer therapies activating the NLRP3 inflammasome have opposing roles. Treatment with the chemotherapeutic drug oxaliplatin leads to the release of ATP from dying cancer cells. ATP interacts with the P2X7 receptor on dendritic cells leading to activation of the NLRP3 inflammasome. IL-1β secreted by dendritic cells primes anti-tumor CD8+ T cells and promotes the anti-tumor response (66). In contrast, gemcitabine (Gem) and 5-fluorouracil (5FU) activate the NLRP3 inflammasome via release of cathepsin B in myeloid derived suppressor cells leading to IL-1β secretion. IL-1β promotes CD4+ T cells to secrete the cytokine IL-17, which blunts the anti-tumor response (67).
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Figure 3: (A) Structure of the NLRP3 inflammasome. (B) Cancer therapies activating the NLRP3 inflammasome have opposing roles. Treatment with the chemotherapeutic drug oxaliplatin leads to the release of ATP from dying cancer cells. ATP interacts with the P2X7 receptor on dendritic cells leading to activation of the NLRP3 inflammasome. IL-1β secreted by dendritic cells primes anti-tumor CD8+ T cells and promotes the anti-tumor response (66). In contrast, gemcitabine (Gem) and 5-fluorouracil (5FU) activate the NLRP3 inflammasome via release of cathepsin B in myeloid derived suppressor cells leading to IL-1β secretion. IL-1β promotes CD4+ T cells to secrete the cytokine IL-17, which blunts the anti-tumor response (67).

Mentions: NLRP3 contains an N-terminal Pyrin domain, a NACHT domain, and a C-terminal LRR as seen in Figure 3A (18). NLRP3 is expressed by a number of cells including epithelial cells, neutrophils, macrophages, and dendritic cells (51, 52). Upon activation, NLRP3 forms a complex with ASC, and caspase-1 leading to pyroptosis and the release of inflammatory cytokines. A number of stimuli are able to activate the NLRP3 inflammasome. Pathogens including Candida albicans, Staphylococcus aureus, and Influenza, among others, have been shown to activate the NLRP3 inflammasome (53–55). Additionally, host-derived stress or danger signals are able to activate the NLRP3 inflammasome, including extracellular ATP and monosodium urate crystals (55–57). Exposure to environmental irritants including silica and asbestos will also lead to activation of the NLRP3 inflammasome (58–60). It is hypothesized that the numerous diverse NLRP3 agonists converge on a common pathway that results in NLRP3 inflammasome activation. Currently, potassium and calcium fluxes along with the generation of reactive oxygen species (ROS) and mitochondrial dysfunction have all been shown to be required for NLRP3 inflammasome activation (61–65).


Beneficial and Detrimental Roles of NLRs in Carcinogenesis.

Janowski AM, Kolb R, Zhang W, Sutterwala FS - Front Immunol (2013)

(A) Structure of the NLRP3 inflammasome. (B) Cancer therapies activating the NLRP3 inflammasome have opposing roles. Treatment with the chemotherapeutic drug oxaliplatin leads to the release of ATP from dying cancer cells. ATP interacts with the P2X7 receptor on dendritic cells leading to activation of the NLRP3 inflammasome. IL-1β secreted by dendritic cells primes anti-tumor CD8+ T cells and promotes the anti-tumor response (66). In contrast, gemcitabine (Gem) and 5-fluorouracil (5FU) activate the NLRP3 inflammasome via release of cathepsin B in myeloid derived suppressor cells leading to IL-1β secretion. IL-1β promotes CD4+ T cells to secrete the cytokine IL-17, which blunts the anti-tumor response (67).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824244&req=5

Figure 3: (A) Structure of the NLRP3 inflammasome. (B) Cancer therapies activating the NLRP3 inflammasome have opposing roles. Treatment with the chemotherapeutic drug oxaliplatin leads to the release of ATP from dying cancer cells. ATP interacts with the P2X7 receptor on dendritic cells leading to activation of the NLRP3 inflammasome. IL-1β secreted by dendritic cells primes anti-tumor CD8+ T cells and promotes the anti-tumor response (66). In contrast, gemcitabine (Gem) and 5-fluorouracil (5FU) activate the NLRP3 inflammasome via release of cathepsin B in myeloid derived suppressor cells leading to IL-1β secretion. IL-1β promotes CD4+ T cells to secrete the cytokine IL-17, which blunts the anti-tumor response (67).
Mentions: NLRP3 contains an N-terminal Pyrin domain, a NACHT domain, and a C-terminal LRR as seen in Figure 3A (18). NLRP3 is expressed by a number of cells including epithelial cells, neutrophils, macrophages, and dendritic cells (51, 52). Upon activation, NLRP3 forms a complex with ASC, and caspase-1 leading to pyroptosis and the release of inflammatory cytokines. A number of stimuli are able to activate the NLRP3 inflammasome. Pathogens including Candida albicans, Staphylococcus aureus, and Influenza, among others, have been shown to activate the NLRP3 inflammasome (53–55). Additionally, host-derived stress or danger signals are able to activate the NLRP3 inflammasome, including extracellular ATP and monosodium urate crystals (55–57). Exposure to environmental irritants including silica and asbestos will also lead to activation of the NLRP3 inflammasome (58–60). It is hypothesized that the numerous diverse NLRP3 agonists converge on a common pathway that results in NLRP3 inflammasome activation. Currently, potassium and calcium fluxes along with the generation of reactive oxygen species (ROS) and mitochondrial dysfunction have all been shown to be required for NLRP3 inflammasome activation (61–65).

Bottom Line: One major source of IL-1β and IL-18 secretion is through the activation of inflammasomes.Inflammasomes are multi-protein complexes that upon activation lead to the processing and secretion of IL-1β and IL-18 mediated by the cysteine protease caspase-1.Here we will discuss recent advances in understanding the mechanism by which NLRs regulate carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Inflammation Program, University of Iowa Carver College of Medicine , Iowa City, IA , USA ; Graduate Program in Immunology, University of Iowa Carver College of Medicine , Iowa City, IA , USA.

ABSTRACT
Inflammation plays a critical role in tumorigenesis and can contribute to oncogenic mutations, tumor promotion, and angiogenesis. Tumor-promoting inflammation is driven by many factors including the presence of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. One major source of IL-1β and IL-18 secretion is through the activation of inflammasomes. Inflammasomes are multi-protein complexes that upon activation lead to the processing and secretion of IL-1β and IL-18 mediated by the cysteine protease caspase-1. Several inflammasomes, including NLRP3, NLRC4, and NLRP6, have been implicated in tumorigenesis. However, inflammasomes play divergent roles in different types of cancer reflecting the complexity of inflammation during tumorigenesis. Understanding the role of inflammasome activation during specific stages of tumorigenesis and also during cancer immunotherapy will help identify novel therapeutic targets that could improve treatment strategies for cancer patients. Here we will discuss recent advances in understanding the mechanism by which NLRs regulate carcinogenesis.

No MeSH data available.


Related in: MedlinePlus