Biology and therapeutic potential of interleukin-10

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Abstract

The authors review the molecular mechanisms regulating IL-10 production and response and describe classic and novel functions of IL-10 in immune and non-immune cells. They further discuss the therapeutic potential of IL-10 in different diseases and the outstanding questions underlying an effective application of IL-10 in clinical settings.

Abstract

The cytokine IL-10 is a key anti-inflammatory mediator ensuring protection of a host from over-exuberant responses to pathogens and microbiota, while playing important roles in other settings as sterile wound healing, autoimmunity, cancer, and homeostasis. Here we discuss our current understanding of the regulation of IL-10 production and of the molecular pathways associated with IL-10 responses. In addition to IL-10’s classic inhibitory effects on myeloid cells, we also describe the nonclassic roles attributed to this pleiotropic cytokine, including how IL-10 regulates basic processes of neural and adipose cells and how it promotes CD8 T cell activation, as well as epithelial repair. We further discuss its therapeutic potential in the context of different diseases and the outstanding questions that may help develop an effective application of IL-10 in diverse clinical settings.

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T cell metabolism drives immunity

Michael D Buck, David O’Sullivan, Erika L Pearce (2015)

Buck et al. discuss the role of lymphocyte metabolism on immune cell development and function.

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Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

B Bennett, R Malefyt, la De … (1991)

In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.

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Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.

Brian Ruffell, Debbie Chang-Strachan, Vivien Chan … (2014)

Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8(+) T cell-dependent, but IL-10 did not directly suppress CD8(+) T cells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL-12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel.

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Author and article information

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J. Exp. Med

Journal ID (publisher-id): jem

Journal ID (hwp): jem

Title: The Journal of Experimental Medicine

Publisher: Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date Collection: 06 January 2020

Publication date (Electronic): 14 October 2019

Volume: 217

Issue: 1

Electronic Location Identifier: e20190418

Affiliations

[1 ]Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

[2 ]Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

[3 ]Department of Immunology, Unité Lymphopoièse, Institut Pasteur, Paris, France

[4 ]University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France

[5 ]Institut National de la Santé et de la Recherche Médicale U1223, Paris, France

[6 ]Laboratory of Immunoregulation and Infection, The Francis Crick Institute, London, UK

[7 ]National Heart and Lung Institute, Imperial College London, UK

Author notes

Correspondence to Anne O’Garra: anne.ogarra@ 123456crick.ac.uk

Author information

Paulo Vieira https://orcid.org/0000-0003-1307-5119

Anne O’Garra https://orcid.org/0000-0001-9845-6134

Article

Publisher ID: 20190418

DOI: 10.1084/jem.20190418

PMC ID: 7037253

PubMed ID: 31611251

SO-VID: db19adff-fa60-41d7-8fa6-793ff049aafb

License:

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

History

Date received : 10 June 2019

Date revision received : 05 August 2019

Date accepted : 11 September 2019

Page count

Pages: 19

Funding

Funded by: Fundo Europeu de Desenvolvimento Regional

Funded by: Fundação para a Ciência e Tecnologia, DOI 10.13039/501100001871;

Award ID: POCI-01-0145-FEDER-007274

Funded by: Fundação para a Ciência e Tecnologia, DOI 10.13039/501100001871;

Funded by: Agence National de la Recherche, DOI 10.13039/501100001665;

Award ID: ANR-13-ISV1-0003-01

Funded by: Institut Pasteur, DOI https://doi.org/10.13039/501100003762;

Funded by: Francis Crick Institute, DOI https://doi.org/10.13039/100010438;

Funded by: Cancer Research UK, DOI https://doi.org/10.13039/501100000289;

Award ID: FC001126

Funded by: UK Medical Research Council, DOI https://doi.org/10.13039/501100000265;

Award ID: FC001126

Funded by: Wellcome Trust, DOI https://doi.org/10.13039/100010269;

Award ID: FC001126

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Biology and therapeutic potential of interleukin-10

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Vascular Biology

Most cited references 201

T cell metabolism drives immunity

Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.

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Cited by 207

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