Mucosal Toll-like Receptor 3-dependent Synthesis of Complement Factor B and Systemic Complement Activation in Inflammatory Bowel Disease

Østvik, Ann Elisabet; Granlund, Atle van Beelen; Gustafsson, Björn; Torp, Sverre Helge; Espevik, Terje; Mollnes, Tom Eirik; Damås, Jan Kristian; Sandvik, Arne K.

doi:10.1097/mib.0000000000000035

Cited by 27 publications

(32 citation statements)

References 38 publications

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“…TLR3 activation stimulates IL-8 release in HT-29 cells [32] in a nucleotide dependent manner (manuscript in preparation). In addition, TLR3 was found to be involved in different cancers [53, 54] and was also reported to affect intestinal inflammation in a complex manner depending on the conditions, either protecting from inflammation or causing epithelial destruction [55–59]. …”

Section: Resultsmentioning

confidence: 99%

Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells

Bahrami

Kukulski

Lecka

et al. 2014

Mediators of Inflammation

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Interleukin-8 (IL-8) plays key roles in both chronic inflammatory diseases and tumor modulation. We previously observed that IL-8 secretion and function can be modulated by nucleotide (P2) receptors. Here we investigated whether IL-8 release by intestinal epithelial HT-29 cells, a cancer cell line, is modulated by extracellular nucleotide metabolism. We first identified that HT-29 cells regulated adenosine and adenine nucleotide concentration at their surface by the expression of the ectoenzymes NTPDase2, ecto-5′-nucleotidase, and adenylate kinase. The expression of the ectoenzymes was evaluated by RT-PCR, qPCR, and immunoblotting, and their activity was analyzed by RP-HPLC of the products and by detection of Pi produced from the hydrolysis of ATP, ADP, and AMP. In response to poly (I:C), with or without ATP and/or ADP, HT-29 cells released IL-8 and this secretion was modulated by the presence of NTPDase2 and adenylate kinase. Taken together, these results demonstrate the presence of 3 ectoenzymes at the surface of HT-29 cells that control nucleotide levels and adenosine production (NTPDase2, ecto-5′-nucleotidase and adenylate kinase) and that P2 receptor-mediated signaling controls IL-8 release in HT-29 cells which is modulated by the presence of NTPDase2 and adenylate kinase.

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Section: Resultsmentioning

confidence: 99%

Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells

Bahrami

Kukulski

Lecka

et al. 2014

Mediators of Inflammation

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“…C3aR, C5aR1, and CR3) regulate TLR‐dependent responses, such as those induced by LPS . Reciprocally, TLR activation induces the expression of complement components, thereby potentially contributing to enhance complement activity in an inflammatory environment . For example, LPS induces robust production and release of factor B of the alternative pathway in macrophages (a major source of extrahepatic complement synthesis) through a TLR4‐TRIF pathway that leads to JNK and NF‐κB activation .…”

Section: Tlr Regulation Of Expression Of Complement Componentsmentioning

confidence: 99%

“…The same study showed that the double‐stranded RNA analog polyI:C (a typical TLR3 agonist) also stimulates factor B production in macrophages via a JNK‐ and NF‐κB‐dependent mechanism; however, this pathway was not mediated by TLR3, suggesting the involvement of alternative receptors for polyI:C, such as the cytosolic sensors MDA‐5 and RIG‐I . An independent study showed that polyI:C induces factor B expression also in colonic epithelial cells, albeit via a TLR3‐dependent mechanism . Importantly, the expression of factor B mRNA and protein is significantly enhanced in colonic biopsies of patients with ulcerative colitis and Crohn's disease as compared to healthy controls .…”

Section: Tlr Regulation Of Expression Of Complement Componentsmentioning

confidence: 99%

“…An independent study showed that polyI:C induces factor B expression also in colonic epithelial cells, albeit via a TLR3‐dependent mechanism . Importantly, the expression of factor B mRNA and protein is significantly enhanced in colonic biopsies of patients with ulcerative colitis and Crohn's disease as compared to healthy controls . Therefore, upon TLR stimulation, innate immune and epithelial cells can locally produce a critical component for alternative complement activation, which can in turn further amplify TLR‐mediated responses.…”

Section: Tlr Regulation Of Expression Of Complement Componentsmentioning

confidence: 99%

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More than complementing Tolls: complement–Toll‐like receptor synergy and crosstalk in innate immunity and inflammation

Hajishengallis

Lambris

2016

Immunological Reviews

124

107

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Summary Complement and Toll-like receptors (TLRs) play key roles in the host immune response and are swiftly activated by infection or other types of immunological stress. This review focuses on the capacity of complement and TLRs to engage in signaling crosstalk, ostensibly to coordinate immune and inflammatory responses through synergistic or antagonistic (regulatory) interactions. However, over-activation or dysregulation of either system may lead – often synergistically – to exaggerated inflammation and host tissue injury. Intriguingly, moreover, certain pathogens can manipulate complement-TLR crosstalk pathways in ways that undermine host immunity and favor their persistence. In the setting of polymicrobial inflammatory disease, subversion of complement-TLR crosstalk by keystone pathogens can promote dysbiosis. Knowledge of the molecular mechanisms underlying complement-TLR crosstalk pathways can, therefore, be used productively for tailored therapeutic approaches, such as, to enhance host immunity, mitigate destructive inflammation, or counteract microbial subversion of the host response.

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“…17 Variations within CFB have been previously associated with age-related macular degeneration 18 and atypical hemolytic uremic syndrome, 19 suggesting its potential role in inflammatory disorders. A recent study 20 showed overexpression of CFB mRNA in inflamed versus normal colonic mucosa of IBD patients, suggesting its role in IBD pathogenesis by inappropriate activation of the complement system, contributing to chronic inflammation, one of the hallmarks of UC. This confirms the role of CFB in UC etiology and further supports our novel GWAS findings.…”

Section: Introductionmentioning

confidence: 99%

A cross-ethnic survey of CFB and SLC44A4, Indian ulcerative colitis GWAS hits, underscores their potential role in disease susceptibility

et al. 2016

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The first ever genome-wide association study (GWAS) of ulcerative colitis in genetically distinct north Indian population identified two novel genes namely CFB and SLC44A4. Considering their biological relevance, we investigated allelic/genetic heterogeneity in these genes among ulcerative colitis cohorts of north Indian, Japanese and Dutch origin using high-density ImmunoChip casecontrol genotype data. Comparative linkage disequilibrium profiling and test of association were performed. Of the 28 CFB SNPs, similar strength of association was observed for rs4151657 (novel ulcerative colitis GWAS SNP) in north Indians (P = 1.73 × 10 − 10 ) and Japanese (P = 2.02 × 10 − 12 ) but not in the Dutch. Further, a three-marker haplotype was shared between north Indians and Japanese (Po10 − 8 ), but a different five-marker haplotype was associated (P = 2.07 × 10 − 6 ) in the Dutch. Of the 22 SLC44A4 SNPs, rs2736428 (novel ulcerative colitis GWAS SNP) was found significantly associated in north Indians (P = 4.94 × 10 − 10 ) and Japanese (P = 3.37 × 10 − 9 ), but not among the Dutch. These results suggest (i) apparent allelic heterogeneity in CFB and genetic heterogeneity in SLC44A4 across different ethnic groups; (ii) shared ulcerative colitis genetic etiological factors among Asians; and finally (iii) re-exploration of GWAS findings together with high-density genotyping/ sequencing and trans-ethnic fine mapping approaches may help identify shared and population-specific risk variants and enable to explain missing disease heritability.

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Mucosal Toll-like Receptor 3-dependent Synthesis of Complement Factor B and Systemic Complement Activation in Inflammatory Bowel Disease

Abstract: Abstract:Background: Recent studies link Toll-like receptor 3 (TLR3) to the pathogenesis of

Cited by 27 publications

References 38 publications

Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells

Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells

More than complementing Tolls: complement–Toll‐like receptor synergy and crosstalk in innate immunity and inflammation

A cross-ethnic survey of CFB and SLC44A4, Indian ulcerative colitis GWAS hits, underscores their potential role in disease susceptibility

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