IL-6, IL-17 and STAT3: a holy trinity in auto-immunity?

Camporeale, Annalisa; Poli, Valeria

doi:10.2741/4054

Cited by 158 publications

(114 citation statements)

References 113 publications

(139 reference statements)

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“…Thus, it is unclear whether B cell-induced IL-6 production directly targets T cells or hepatocytes to modulate transporter expression. Given that IL-6-gp130-STAT3 in T cells promotes IL-17-producing CD4 T cells (Camporeale and Poli, 2012), we were surprised by the low levels of IL-17 expression in LPS-treated Rag1 KO mice. However, these results suggest that hepatocytes may be the critical recipient of the IL-6 signaling during acute TLR4-mediated inflammation.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Hepatic Organic Cation Transporter 1, Organic Anion-Transporting Polypeptide 1a4, Bile-Salt Export Pump, and Multidrug Resistance-Associated Protein 2 Transporter Expression in Lymphocyte-Deficient Mice Associates with Interleukin-6 Production

Bodeman

Dzierlenga

Tally

et al. 2013

J Pharmacol Exp Ther

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Cholestasis results from interrupted bile flow and is associated with immune-mediated liver diseases. It is unclear how inflammation contributes to cholestasis. The aim of this study was to determine whether T and B cells contribute to hepatic transporter expression under basal and inflammatory conditions. C57BL/6J wild-type mice or strains lacking T, B, or both T and B cells were exposed to lipopolysaccharide (LPS) or saline, and livers were collected 16 hours later. Branched DNA signal amplification was used to assess mRNA levels of organic anion-transporting polypeptides (Oatp) 1a1, 1a4, and 1b2; organic cation transporter (Oct) 1; canalicular bile-salt export pump (Bsep); multidrug resistance-associated proteins (Mrp) 2 and 3; and sodium-taurocholate cotransporting polypeptide (Ntcp). Real-time polymerase chain reaction analysis was used to correlate changes of transporter expression with interleukin-1b (IL-1b), IL-6, IL-17A, IL-17F, tumor necrosis factor-a (TNF-a), and interferon-g expression in the liver. LPS treatment inhibited Bsep and Oct1 mRNA expression, and this was abrogated with a loss of T cells, but not B cells. In addition, the absence of T cells increased Mrp2 mRNA expression, whereas B cell deficiency attenuated Oatp1a4 mRNA in LPS-treated mice. Oatp1a1, Oatp1b2, Ntcp, and Mrp3 were largely unaffected by T or B cell deficiency. Lymphocyte deficiency altered basal and inflammatory IL-6, but not TNF-a or IL-1b, mRNA expression. Taken together, these data implicate lymphocytes as regulators of basal and inflammatory hepatic transporter expression and suggest that IL-6 signaling may play a critical role.

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Section: Discussionmentioning

confidence: 99%

Differential Regulation of Hepatic Organic Cation Transporter 1, Organic Anion-Transporting Polypeptide 1a4, Bile-Salt Export Pump, and Multidrug Resistance-Associated Protein 2 Transporter Expression in Lymphocyte-Deficient Mice Associates with Interleukin-6 Production

Bodeman

Dzierlenga

Tally

et al. 2013

J Pharmacol Exp Ther

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“…Previous studies have shown that IL-6 is a pleiotropic cytokine involved in the cross talk between immune cells and stromal cells, activates the STAT3 signaling axis, is one of the main regulators of Th17 cell differentiation (46), and promotes IL-22 expression (24). IL-6-deficient mice showed an impaired defense against pneumococcal pneumonia (47).…”

Section: Discussionmentioning

confidence: 99%

Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia

et al. 2015

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c Th17 immunity in the gastrointestinal tract is regulated by the intestinal microbiota composition, particularly the presence of segmented filamentous bacteria (sfb), but the role of the intestinal microbiota in pulmonary host defense is not well explored. We tested whether altering the gut microbiota by acquiring sfb influences the susceptibility to staphylococcal pneumonia via induction of type 17 immunity. Groups of C57BL/6 mice which differed in their intestinal colonization with sfb were challenged with methicillin-resistant Staphylococcus aureus in an acute lung infection model. Bacterial burdens, bronchoalveolar lavage fluid (BALF) cell counts, cell types, and cytokine levels were compared between mice from different vendors, mice from both vendors after cohousing, mice given sfb orally prior to infection, and mice with and without exogenous interleukin-22 (IL-22) or anti-IL-22 antibodies. Mice lacking sfb developed more severe S. aureus pneumonia than mice colonized with sfb, as indicated by higher bacterial burdens in the lungs, lung inflammation, and mortality. This difference was reduced when sfb-negative mice acquired sfb in their gut microbiota through cohousing with sfb-positive mice or when given sfb orally. Levels of type 17 immune effectors in the lung were higher after infection in sfb-positive mice and increased in sfb-negative mice after acquisition of sfb, as demonstrated by higher levels of IL-22 and larger numbers of IL-22؉ TCR␤ ؉ cells and neutrophils in BALF. Exogenous IL-22 protected mice from S. aureus pneumonia. The murine gut microbiota, particularly the presence of sfb, promotes pulmonary type 17 immunity and resistance to S. aureus pneumonia, and IL-22 protects against severe pulmonary staphylococcal infection.

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“…To note, the slightly increased, although nonsignificant, level of IL-6 found early after AP challenge only in the BALFs of the asthmatic untreated mice might suggest the involvement of the IL-17 axis in the AP-induced OA phenotype. IL-6 has recently emerged as main regulator of the differentiation and function of Th17 cells [33]. Thus, further research is needed to confirm the occurrence of Th17-driven airway inflammation in our AP-induced neutrophilic asthma model and its therapeutic reduction by hASCs, analogously to other recently reported Th17-driven neutrophilic asthma models [28].…”

Section: Figmentioning

confidence: 99%

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

Martínez-González

Cruz

Moreno

et al. 2014

Stem Cells and Development

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Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 · 10 6 cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the APinjured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA.

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IL-6, IL-17 and STAT3: a holy trinity in auto-immunity?

Cited by 158 publications

References 113 publications

Differential Regulation of Hepatic Organic Cation Transporter 1, Organic Anion-Transporting Polypeptide 1a4, Bile-Salt Export Pump, and Multidrug Resistance-Associated Protein 2 Transporter Expression in Lymphocyte-Deficient Mice Associates with Interleukin-6 Production

Differential Regulation of Hepatic Organic Cation Transporter 1, Organic Anion-Transporting Polypeptide 1a4, Bile-Salt Export Pump, and Multidrug Resistance-Associated Protein 2 Transporter Expression in Lymphocyte-Deficient Mice Associates with Interleukin-6 Production

Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

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