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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 NLRP12. (B) When NLRP12 is present in intestinal epithelial cells it interacts with TRAF3 leading to stabilization of TRAF3 levels. Stabilization of TRAF3 leads to regulation of the non-canonical NF-κB pathway and diminished levels of the chemokines CXCL12 and CXCL13, both of which are upregulated in human cancers. Regulation of the non-canonical NF-κB pathway by NLRP12 leads to decreased inflammation and tumorigenesis in the colon (17).
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Figure 4: (A) Structure of NLRP12. (B) When NLRP12 is present in intestinal epithelial cells it interacts with TRAF3 leading to stabilization of TRAF3 levels. Stabilization of TRAF3 leads to regulation of the non-canonical NF-κB pathway and diminished levels of the chemokines CXCL12 and CXCL13, both of which are upregulated in human cancers. Regulation of the non-canonical NF-κB pathway by NLRP12 leads to decreased inflammation and tumorigenesis in the colon (17).

Mentions: NLRP12, also known as Monarch-1, is composed of an N-terminal Pyrin domain, an NACHT domain, and a C-terminal LRR (78) as shown in Figure 4A. NLRP12 was shown to associate with ASC in an overexpression system; however, whether NLRP12 forms a functional inflammasome has not been well documented (79). NLRP12 is highly expressed in granulocytes in the bone marrow, and also macrophages in the spleen (80). Currently, NLRP12 is viewed as a regulator of inflammation. However, NLRP12 has been shown to have opposing roles in activation of NF-κB. Transient transfection of 293T cells with NLRP12 and ASC constructs led to transcription of an NF-κB luciferase reporter, demonstrating a role for NLRP12 in the activation of NF-κB (79). NLRP12 seems to inhibit the non-canonical NF-κB activation in the human monocytic cell line THP-1 by the binding of NLRP12 to NF-κB inducing kinase (NIK) and leading to the degradation of NIK (81). Interestingly, in humans, mutations in NLRP12 have been associated with a periodic fever syndrome (82, 83). When HEK293T cells were transfected with NLRP12 constructs harboring these mutations, an increase of NF-κB activation was seen (82). Missense mutations in NLRP12 in periodic fever syndrome were also associated with increased caspase-1 activation and had no effect on NF-κB (83, 84). These data further demonstrate NLRP12 as a potential negative regulator of inflammation and imply that NLRP12 may play a causal role in certain human disease.


Beneficial and Detrimental Roles of NLRs in Carcinogenesis.

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

(A) Structure of NLRP12. (B) When NLRP12 is present in intestinal epithelial cells it interacts with TRAF3 leading to stabilization of TRAF3 levels. Stabilization of TRAF3 leads to regulation of the non-canonical NF-κB pathway and diminished levels of the chemokines CXCL12 and CXCL13, both of which are upregulated in human cancers. Regulation of the non-canonical NF-κB pathway by NLRP12 leads to decreased inflammation and tumorigenesis in the colon (17).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: (A) Structure of NLRP12. (B) When NLRP12 is present in intestinal epithelial cells it interacts with TRAF3 leading to stabilization of TRAF3 levels. Stabilization of TRAF3 leads to regulation of the non-canonical NF-κB pathway and diminished levels of the chemokines CXCL12 and CXCL13, both of which are upregulated in human cancers. Regulation of the non-canonical NF-κB pathway by NLRP12 leads to decreased inflammation and tumorigenesis in the colon (17).
Mentions: NLRP12, also known as Monarch-1, is composed of an N-terminal Pyrin domain, an NACHT domain, and a C-terminal LRR (78) as shown in Figure 4A. NLRP12 was shown to associate with ASC in an overexpression system; however, whether NLRP12 forms a functional inflammasome has not been well documented (79). NLRP12 is highly expressed in granulocytes in the bone marrow, and also macrophages in the spleen (80). Currently, NLRP12 is viewed as a regulator of inflammation. However, NLRP12 has been shown to have opposing roles in activation of NF-κB. Transient transfection of 293T cells with NLRP12 and ASC constructs led to transcription of an NF-κB luciferase reporter, demonstrating a role for NLRP12 in the activation of NF-κB (79). NLRP12 seems to inhibit the non-canonical NF-κB activation in the human monocytic cell line THP-1 by the binding of NLRP12 to NF-κB inducing kinase (NIK) and leading to the degradation of NIK (81). Interestingly, in humans, mutations in NLRP12 have been associated with a periodic fever syndrome (82, 83). When HEK293T cells were transfected with NLRP12 constructs harboring these mutations, an increase of NF-κB activation was seen (82). Missense mutations in NLRP12 in periodic fever syndrome were also associated with increased caspase-1 activation and had no effect on NF-κB (83, 84). These data further demonstrate NLRP12 as a potential negative regulator of inflammation and imply that NLRP12 may play a causal role in certain human disease.

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