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Review
. 2015 Jul;74(1):27-34.
doi: 10.1016/j.cyto.2014.10.031. Epub 2014 Dec 4.

Interleukin-10 Paradox: A Potent Immunoregulatory Cytokine That Has Been Difficult to Harness for Immunotherapy

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Free PMC article
Review

Interleukin-10 Paradox: A Potent Immunoregulatory Cytokine That Has Been Difficult to Harness for Immunotherapy

Ankit Saxena et al. Cytokine. .
Free PMC article

Abstract

Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.

Keywords: Autoimmunity; B-cells; Fas pathway; Interleukin-10; gld.

Conflict of interest statement

The authors have no financial conflict of interest.

Figures

Figure 1
Figure 1. Effects of IL-10 on pathogenesis of the indicated systemic- and organ-specific autoimmune diseases
The solid arrow shows promotion of autoimmunity, T line indicates inhibition, whereas broken lines indicate inconclusive effect. Clinical trials for IBD and Psoriasis are completed and for RA are still ongoing. No reported clinical trials for other diseases [59]
Figure 2
Figure 2. Inactivating Fas pathway restores a protective role for IL-10 against insulitis in NOD mice
Images show that the gld mutation of FasL protects pancreatic islets against insulitis. The model depicts how interaction of IL-10-secreting CD5+ B cells with local FasL sources could lead to their deletion and depriving of the host of a critical source of protective IL-10 [70].

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