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Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1? and tumor necrosis factor ?.

ABSTRACT: Endometriosis are characterized by dense fibrous tissue. Numerous studies have investigated roles of inflammation on the pathophysiology of endometriosis. However, the interplay of inflammation and fibrosis remains to be clarified. Here we show that low levels of interleukin-1? (IL-1?) and tumor necrosis factor-alpha (TNF?) promoted a fibrotic phenotype, whereas high levels of IL-1? and TNF? inactivated the fibrotic phenotype of endometriotic stromal cells (Ectopic-ES). IL-1? 10?pg/mL and TNF? 100 and 1,000?pg/mL had minimal effects, whereas the highest dose of IL-1? (100?pg/mL) significantly decreased collagen gel contraction in Ectopic-ES. Furthermore, in Ectopic-ES, low levels of IL-1? (1?pg/mL) and/or TNF? 10?pg/mL significantly increased Col I mRNA expression, whereas higher doses of IL-1? (10 and/or 100?pg/mL) and/or TNF? (100 and/or 1,000?pg/mL) significantly decreased Col I and/or ?SMA mRNA expression and the percentage of cells with Col I?+?and/or ?SMA?+?stress fibers. In contrast, in either menstrual endometrial stromal cells of patients with endometriosis or those of healthy women, varying doses of IL-1? and/or TNF? had no significant effects on either Col I or ?SMA mRNA/protein expression. The present findings bring into question whether we should still continue to attempt anti-inflammatory treatment strategies for endometriosis.

SUBMITTER: Matsuzaki S

PROVIDER: S-EPMC7289797 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α.

Matsuzaki Sachiko S Pouly Jean-Luc JL Canis Michel M

Scientific reports 20200611 1

Endometriosis are characterized by dense fibrous tissue. Numerous studies have investigated roles of inflammation on the pathophysiology of endometriosis. However, the interplay of inflammation and fibrosis remains to be clarified. Here we show that low levels of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNFα) promoted a fibrotic phenotype, whereas high levels of IL-1β and TNFα inactivated the fibrotic phenotype of endometriotic stromal cells (Ectopic-ES). IL-1β 10 pg/mL and TNFα 1 ...[more]

PMID: 32528066

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Project description:ObjectiveIn this work, we examine the molecular basis for capillary tube regression and identify key proregressive factors, signaling pathways, and pharmacological antagonists of this process. Approach and Results: We demonstrate that the proinflammatory mediators, IL (interleukin)-1β, TNF (tumor necrosis factor) α, and thrombin, singly and in combination, are potent regulators of capillary tube regression in vitro. These proregressive factors, when added to endothelial cell-pericyte cocultures, led to selective loss of endothelial cell-lined tube networks, with retention and proliferation of pericytes despite the marked destruction of adjacent capillary tubes. Moreover, treatment of macrophages with the TLR (toll-like receptor) agonists Pam3CSK4 and lipopolysaccharide generates conditioned media with marked proregressive activity, that is completely blocked by a combination of neutralizing antibodies directed to IL-1β and TNFα but not to other factors. The same combination of blocking antibodies, as well as the anti-inflammatory cytokine IL-10, interfere with macrophage-dependent hyaloid vasculature regression in mice suggesting that proinflammatory cytokine signaling regulates capillary regression in vivo. In addition, we identified a capillary regression signaling signature in endothelial cells downstream of these proregressive agents that is characterized by increased levels of ICAM-1 (intercellular adhesion molecule-1), phospho-p38, and phospho-MLC2 (myosin light chain-2) and decreased levels of phospho-Pak2, acetylated tubulin, phospho-cofilin, and pro-caspase3. Finally, we identified combinations of pharmacological agents (ie, FIST and FISTSB) that markedly rescue the proregressive activities of IL-1β, TNFα, and thrombin, individually and in combination.ConclusionsOverall, these new studies demonstrate that the major proinflammatory mediators, IL-1β, TNFα, and thrombin, are key regulators of capillary tube regression-a critical pathological process regulating human disease.

Dataset Information

Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1? and tumor necrosis factor ?.

Publications

Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α.

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