Interleukine 6 | EPFL Graph Search

L'interleukine 6 (IL6) est une cytokine appartenant au trio des cytokines pro-inflammatoires de l'immunité innée (l'interleukine-1, l' interleukine-6 et le facteur de nécrose tumorale) dans la phase aiguë de l'inflammation (il s'agit d'une cytokine pro-inflammatoire). Elle stimule notamment la sécrétion des protéines de la phase aiguë au cours de la réaction du système immunitaire innée (APP, ou acute phase protein). Son gène est IL6 situé sur le chromosome 7 humain. Dix cytokines de la famille IL-6 ont été identifiées : IL-6, oncostatine M (OSM), facteur inhibiteur de leucémie (LIF), facteur neurotrophique ciliaire (CNTF), cardiotropine-1 (CT-1), cytokine de type cardiotrophine (CLC) , neuropoïétine (NP), IL-11, IL-27 et IL-31. Toutes ces cytokines partagent la glycoprotéine membranaire gp130 en tant que récepteur commun et sous-unité de transducteur de signal dans leurs complexes récepteurs, à l'exception de l'IL-31. L'interleukine 6 est une cytokine clé dans la régulation de l'in

Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism

Ludger Jan Elzuë Goeminne, Vera Monica Lemos Da Silva, Barbara Moreira Crisol, Eduardo Rochete Ropelle

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation– and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.

2022

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8(+) T cells

Douglas Hanahan, Maria Karagianni, Petra Catalina Schwalie, Mélanie Louise Tichet, Stephan Wullschleger

Expansion and differentiation of antigen-experienced PD-1(+)TCF-1(+) stem-like CD8(+) T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade(1-4). Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8(+) T cells similar to those generated in an acute infection(5). IL-2 binding to the IL-2 receptor alpha-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor beta- and gamma-chain (IL-2R beta gamma)-biased agonists are currently being developed(6-10). Here we show that IL-2R beta gamma-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2R beta gamma on the same cell recovers the ability to differentiate stem-like CD8(+) T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

NATURE PORTFOLIO2022

RIP4 inhibits STAT3 signaling to sustain lung adenocarcinoma differentiation

Paolo Angelino, Johanna Pauline Chiffelle, Mauro Delorenzi, Jawahar Kopparam, Etienne Meylan, Alessandra Piersigilli, Nadine Zangger

Loss of epithelial differentiation and extracellular matrix (ECM) remodeling are known to facilitate cancer progression and are associated with poor prognosis in patients with lung cancer. We have identified Receptor-interacting serine/threonine protein kinase 4 (RIP4) as a regulator of tumor differentiation in lung adenocarcinoma (AC). Bioinformatics analyses of human lung AC samples showed that poorly differentiated tumors express low levels of RIP4, whereas high levels are associated with better overall survival. In vitro, lung tumor cells expressing reduced RIP4 levels showed enhanced activation of STAT3 signaling and had a greater ability to invade through collagen. In contrast, overexpression of RIP4 inhibited STAT3 activation, which abrogated interleukin-6-dependent induction of lysyl oxidase, a collagen cross-linking enzyme. In an autochthonous mouse model of lung AC initiated by Kras(G12D) expression with loss of p53, Rip4 knockdown tumors progressed to a poorly differentiated state marked by an increase in Hmga2, reduced Ttf1, and enrichment of genes regulating extracellular remodeling and Jak-Stat signaling. Tail vein injections of cells overexpressing Rip4 showed a reduced potential to invade and form tumors, which was restored by co-expression of Stat3. Altogether, our work has identified that loss of RIP4 enhances STAT3 signaling in lung cancer cells, promoting the expression of ECM remodeling genes and cancer dedifferentiation.

Nature Publishing Group2017

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8(+) T cells

Douglas Hanahan, Maria Karagianni, Petra Catalina Schwalie, Mélanie Louise Tichet, Stephan Wullschleger

NATURE PORTFOLIO2022