Interleukin-1β Modulates Proinflammatory Cytokine Production in Human Epithelial Cells

Eskan, Mehmet A.; Benakanakere, Manjunatha R.; Rose, Beate G.; Zhang, Ping; Zhao, Jiawei; Stathopoulou, Panagiota G.; Fujioka, Daisuke; Kinane, Denis F.

doi:10.1128/iai.01428-07

Cited by 94 publications

(76 citation statements)

References 31 publications

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“…As with IL-6 (31), IL-1b secretion is increased in WAT during obesity (32), and both cytokines are known to act in concert in diverse biological process (33). Il-1b is also implicated in a "secondary" inflammatory response, regulating the production of cytokines and chemokines as G-CSF, IL-6, or IL-8 (34)(35)(36). Interestingly, our study showed that neutralization of IL-6 and IL-1b in cocultures led to a decreased inflammatory response and a rescue of some metabolic and secretory alterations of adipocytes (i.e., G-CSF, CXCLs, and IL-8).…”

Section: Discussionmentioning

confidence: 99%

Endothelial Cells From Visceral Adipose Tissue Disrupt Adipocyte Functions in a Three-Dimensional Setting: Partial Rescue by Angiopoietin-1

Pellegrinelli

Rouault

Veyrie³

et al. 2014

Diabetes

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During obesity, chronic inflammation of human white adipose tissue (WAT) is associated with metabolic and vascular alterations. Endothelial cells from visceral WAT (VAT-ECs) exhibit a proinflammatory and senescent phenotype and could alter adipocyte functions. We aimed to determine the contribution of VAT-ECs to adipocyte dysfunction related to inflammation and to rescue these alterations by antiinflammatory strategies. We developed an original three-dimensional setting allowing maintenance of unilocular adipocyte functions. Coculture experiments demonstrated that VAT-ECs provoked a decrease in the lipolytic activity, adipokine secretion, and insulin sensitivity of adipocytes from obese subjects, as well as an increased production of several inflammatory molecules. Interleukin (IL)-6 and IL-1b were identified as potential actors in these adipocyte alterations. The inflammatory burst was not observed in cocultured cells from lean subjects. Interestingly, pericytes, in functional interactions with ECs, exhibited a proinflammatory phenotype with diminished angiopoietin-1 (Ang-1) secretion in WAT from obese subjects. Using the anti-inflammatory Ang-1, we corrected some deleterious effects of WAT-ECs on adipocytes, improving lipolytic activity and insulin sensitivity and reducing the secretion of proinflammatory molecules. In conclusion, we identified a negative impact of VAT-ECs on adipocyte functions during human obesity. Therapeutic options targeting EC inflammation could prevent adipocyte alterations that contribute to obesity comorbidities.

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Section: Discussionmentioning

confidence: 99%

Endothelial Cells From Visceral Adipose Tissue Disrupt Adipocyte Functions in a Three-Dimensional Setting: Partial Rescue by Angiopoietin-1

Pellegrinelli

Rouault

Veyrie³

et al. 2014

Diabetes

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“…They were grown as previously described (28) to sub-confluence, sub-cultured, and challenged as described (2,29,30). At confluence, they were challenged with heat-inactivated P. gingivalis (strain 33277) or 1 g/ml FSL-1 (Pam2CGDPKHPKSF, a synthetic diacylated lipoprotein and a specific ligand for TLR-2) (InvivoGen, CA).…”

Section: Methodsmentioning

confidence: 99%

Modulation of TLR2 Protein Expression by miR-105 in Human Oral Keratinocytes

Benakanakere¹,

Li²,

Eskan³

et al. 2009

Journal of Biological Chemistry

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133

107

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Mammalian biological processes such as inflammation, involve regulation of hundreds of genes controlling onset and termination. MicroRNAs (miRNAs) can translationally repress target mRNAs and regulate innate immune responses. Our model system comprised primary human keratinocytes, which exhibited robust differences in inflammatory cytokine production (interleukin-6 and tumor necrosis factor-␣) following specific Toll-like receptor 2 and 4 (TLR-2/TLR-4) agonist challenge. We challenged these primary cells with Porphyromonas gingivalis (a Gram-negative bacterium that triggers TLR-2 and TLR-4) and performed miRNA expression profiling. We identified miRNA (miR)-105 as a modulator of TLR-2 protein translation in human gingival keratinocytes. There was a strong inverse correlation between cells that had high cytokine responses following TLR-2 agonist challenge and miR-105 levels. Knock-in and knock-down of miR-105 confirmed this inverse relationship. In silico analysis predicted that miR-105 had complementarity for TLR-2 mRNA, and the luciferase reporter assay verified this. Further understanding of the role of miRNA in host responses may elucidate disease susceptibility and suggest new anti-inflammatory therapeutics.

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“…2A). The time points for this chronic infection were carefully chosen based on our previously published results on P. gingivalisinduced inflammatory cytokine response in gingival epithelial cells (Eskan et al 2008;Stathopoulou et al 2009;Stathopoulou et al 2010). By using this method, we successfully induced tolerance to P. gingivalis (live bacteria at MOI: 5) in normal epithelial cells.…”

Section: Chronic P Gingivalis Infection Modelmentioning

confidence: 99%

TLR2 Promoter Hypermethylation Creates Innate Immune Dysbiosis

et al. 2014

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Periodontitis is a common chronic inflammatory disease that is initiated by a complex microbial biofilm that poses significant health and financial burdens globally. Porphyromonas gingivalis is a predominant pathogen that maintains chronic inflammatory periodontitis. Toll-like receptors (TLRs) play an important role in periodontitis by recognizing pathogens and maintaining tissue homeostasis. Deficiencies in TLR expression and downstream signaling may reduce the host's innate defenses against pathogens, leading to bacterial persistence and exacerbated inflammation, which are now being better appreciated in disease pathologies. In the case of periodontitis, gingival epithelial cells form the first line of defense against pathogens. Innate immune dysregulation in these cells relates to severe disease pathology. We recently identified a blunted TLR2 expression in certain gingival epithelial cells expressing diminished cytokine signaling upon P. gingivalis stimulation. Upon detailed analysis of the TLR2 promoter CpG Island, we noted higher CpG methylation in this dysregulated cell type. When these cells were treated with DNA methyltransferase inhibitor, TLR2 mRNA and cytokine expression were significantly increased. If TLR2 expression plasmid was ectopically expressed in dysfunctional cells prior to P. gingivalis stimulation, the cytokine expression was increased, confirming the requirement of TLR2 in the P. gingivalis-mediated inflammatory response. We designed a chronic in vitro infection model to test if P. gingivalis can induce DNA methylation in normal gingival epithelial cells that express higher TLR2 upon agonist stimulation. Chronic treatment of normal epithelial cells with P. gingivalis introduced de novo DNA methylation within the cells. In addition, increased DNA methylation was observed in the gingiva of mice infected with P. gingivalis in a periodontitis oral gavage model. Moreover, tissues obtained from periodontitis patients also exhibited differential TLR2 promoter methylation, as revealed by bisulfite DNA sequencing. Taken together, DNA methylation of TLR2 can modulate host innate defense mechanisms that may confer increased disease susceptibility.

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Interleukin-1β Modulates Proinflammatory Cytokine Production in Human Epithelial Cells

Cited by 94 publications

References 31 publications

Endothelial Cells From Visceral Adipose Tissue Disrupt Adipocyte Functions in a Three-Dimensional Setting: Partial Rescue by Angiopoietin-1

Endothelial Cells From Visceral Adipose Tissue Disrupt Adipocyte Functions in a Three-Dimensional Setting: Partial Rescue by Angiopoietin-1

Modulation of TLR2 Protein Expression by miR-105 in Human Oral Keratinocytes

TLR2 Promoter Hypermethylation Creates Innate Immune Dysbiosis

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