Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease

Cepero-Donates, Yuneivy; Lacraz, Grégory; Ghobadi, Farnaz; Rakotoarivelo, Volatiana; Orkhis, Sakina; Mayhue, Marian; Chen, Yi Guang; Rola‐Pleszczynski, Marek; Menéndez, Alfredo; Ilangumaran, Subburaj; Ramanathan, Sheela

doi:10.1016/j.cyto.2016.01.020

Cited by 54 publications

(47 citation statements)

References 65 publications

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“…Molecules that are part of the neurotrophic signaling are highlighted in red in the diagram; IL15, EIF2AK3 (PERK), F2RL1 (PAR2) are shown in blue. These genes are known to be associated with the inflammatory response [27][28][29][30][31][32].…”

Section: The Relationship Between Key Genes and Signaling Pathwaysmentioning

confidence: 99%

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Orekhov

Sukhorukov

Nikiforov

et al. 2020

IJMS

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Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our Int.Int. J. Mol. Sci. 2020, 21, 2716 2 of 17 group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

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Section: The Relationship Between Key Genes and Signaling Pathwaysmentioning

confidence: 99%

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Orekhov

Sukhorukov

Nikiforov

et al. 2020

IJMS

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“…In addition, several mediators have been demonstrated which play a positive role in regulating inflammation in the context of NAFLD. For example, IL-15 upregulates expression of chemokines like CCL2, CCL5, and CXCL10 and increases infiltration of mononuclear cells, promoting inflammation in NAFLD [70]. Tumor necrosis factor receptor-associated factor 1 (TRAF1), an important adapter protein, is extensively implicated in mediating immunity/inflammation and cell death.…”

Section: The Relationship and Interdependence Between Oxidative Stmentioning

confidence: 99%

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

Hong

Tan

et al. 2016

Oxidative Medicine and Cellular Longevity

272

179

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The crucial roles of oxidative stress and inflammation in the development of hepatic diseases have been unraveled and emphasized for decades. From steatosis to fibrosis, cirrhosis and liver cancer, hepatic oxidative stress, and inflammation are sustained and participated in this pathological progressive process. Notably, increasing evidences showed that oxidative stress and inflammation are tightly related, which are regarded as essential partners that present simultaneously and interact with each other in various pathological conditions, creating a vicious cycle to aggravate the hepatic diseases. Clarifying the interaction of oxidative stress and inflammation is of great importance to provide new directions and targets for developing therapeutic intervention. Herein, this review is concerned with the regulation and interdependence of oxidative stress and inflammation in a variety of liver diseases. In addition to classical mediators and signaling, particular emphasis is placed upon immune suppression, a potential linkage of oxidative stress and inflammation, to provide new inspiration for the treatment of liver diseases. Furthermore, since antioxidation and anti-inflammation have been extensively attempted as the strategies for treatment of liver diseases, the application of herbal medicines and their derived compounds that protect liver from injury via regulating oxidative stress and inflammation collectively were reviewed and discussed.

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“…21,22,23), type I diabetes 6,24 and non-alcoholic fatty liver disease. 25 Thus, IL-15 represents an attractive target for several human pathologies with high medical need. There is, however, no approved treatment that specifically neutralizes IL-15, despite some early encouraging studies of a monoclonal antibody in rheumatoid arthritis patients.…”

Section: Introductionmentioning

confidence: 99%

Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis

Vicari¹,

Schoepfer

Meresse

et al. 2017

mAbs

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Interleukin-15 (IL-15) is a critical regulator of immune responses, especially at mucosal interfaces within the gastro-intestinal tract. Here, we describe the discovery and characterization of a humanized antibody to IL-15. Data from its epitope and mode of action, cell biology and primate pharmacology, as well as translational studies in human samples and in vivo proof-of-concept experiments in mouse models demonstrate the therapeutic potential of this new antibody targeting IL-15 for refractory celiac disease and eosinophilic esophagitis.

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Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease

Cited by 54 publications

References 65 publications

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis

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