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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 NLRC4 inflammasome and NAIP proteins. (B) Summary of immunotherapy utilizing activation of NLRC4 (43). EL4 thymoma cells were transduced to express flagellin from S. typhimurium. Mice were then immunized with irradiated EL4 cells expressing flagellin. Flagellin is recognized by TLR5 and NLRC4 in the presence of tumor antigens leading to production of pro-inflammatory cytokines and an enhanced anti-tumor CD8+ T cell response.
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Figure 1: (A) Structure of the NLRC4 inflammasome and NAIP proteins. (B) Summary of immunotherapy utilizing activation of NLRC4 (43). EL4 thymoma cells were transduced to express flagellin from S. typhimurium. Mice were then immunized with irradiated EL4 cells expressing flagellin. Flagellin is recognized by TLR5 and NLRC4 in the presence of tumor antigens leading to production of pro-inflammatory cytokines and an enhanced anti-tumor CD8+ T cell response.

Mentions: The PRR NLRC4 contains an N-terminal caspase activation and recruitment domain (CARD), a central NACHT domain, and a C-terminal LRR as depicted in Figure 1A (28, 29). The CARD domain present in NLRC4 allows for direct interaction with pro-caspase-1 (28). However, optimal caspse-1 activation requires the adaptor protein ASC (30–32). NLRC4 is classically understood to recognize a number of Gram-negative bacteria including Salmonella enterica, Anaplasma phagocytophilum, Pseudomonas aeruginosa, and Legionella pneumophila, which in turn leads to subsequent activation of the NLRC4 inflammasome (31, 33–35). More specifically, cytosolic flagellin and proteins with structural homology to flagellin such as PrgJ, a component of type III secretion systems, have also been shown to activate the NLRC4 inflammasome (36–38). The NLRC4 inflammasome works in concert with neuronal apoptosis inhibitor protein (NAIP) 2 to recognize PrgJ-like proteins and NAIP5 to recognize cytosolic flagellin (39–41). NAIP proteins, like NLRC4, have a C-terminal LRR domain, a central NACHT domain, and an N-terminal baculovirus IAP repeat (BIR) instead of the CARD domain (42).


Beneficial and Detrimental Roles of NLRs in Carcinogenesis.

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

(A) Structure of the NLRC4 inflammasome and NAIP proteins. (B) Summary of immunotherapy utilizing activation of NLRC4 (43). EL4 thymoma cells were transduced to express flagellin from S. typhimurium. Mice were then immunized with irradiated EL4 cells expressing flagellin. Flagellin is recognized by TLR5 and NLRC4 in the presence of tumor antigens leading to production of pro-inflammatory cytokines and an enhanced anti-tumor CD8+ T cell response.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: (A) Structure of the NLRC4 inflammasome and NAIP proteins. (B) Summary of immunotherapy utilizing activation of NLRC4 (43). EL4 thymoma cells were transduced to express flagellin from S. typhimurium. Mice were then immunized with irradiated EL4 cells expressing flagellin. Flagellin is recognized by TLR5 and NLRC4 in the presence of tumor antigens leading to production of pro-inflammatory cytokines and an enhanced anti-tumor CD8+ T cell response.
Mentions: The PRR NLRC4 contains an N-terminal caspase activation and recruitment domain (CARD), a central NACHT domain, and a C-terminal LRR as depicted in Figure 1A (28, 29). The CARD domain present in NLRC4 allows for direct interaction with pro-caspase-1 (28). However, optimal caspse-1 activation requires the adaptor protein ASC (30–32). NLRC4 is classically understood to recognize a number of Gram-negative bacteria including Salmonella enterica, Anaplasma phagocytophilum, Pseudomonas aeruginosa, and Legionella pneumophila, which in turn leads to subsequent activation of the NLRC4 inflammasome (31, 33–35). More specifically, cytosolic flagellin and proteins with structural homology to flagellin such as PrgJ, a component of type III secretion systems, have also been shown to activate the NLRC4 inflammasome (36–38). The NLRC4 inflammasome works in concert with neuronal apoptosis inhibitor protein (NAIP) 2 to recognize PrgJ-like proteins and NAIP5 to recognize cytosolic flagellin (39–41). NAIP proteins, like NLRC4, have a C-terminal LRR domain, a central NACHT domain, and an N-terminal baculovirus IAP repeat (BIR) instead of the CARD domain (42).

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