Interleukin‐10: new perspectives on an old cytokine

Abstract

Summary Interleukin-10 (IL-10) has long been recognized to have potent and broad-spectrum anti-inflammatory activity, which has been unequivocally established in various models of infection, inflammation, and even in cancer. However, because of the marginal successes of the initial clinical trials using recombinant IL-10, some of the interest in this cytokine as an anti-inflammatory therapeutic has diminished. New work showing IL-10 production from regulatory T cells and even T-helper 1 T cells has reinvigorated the field and revealed the power of this cytokine to influence immune responses. Furthermore, new preclinical studies suggest that combination therapies, using antibodies to IL-10 along with chemotherapy, can be effective in treating bacterial, viral, or neoplastic diseases. Studies to understand IL-10 gene expression in the various cell types may lead to new therapeutics to enhance or inhibit IL-10 production. In this review, we summarize what is known about the regulation of IL-10 gene expression by various immune cells. We speculate on the promise that this cytokine holds to influence immune responses and mitigate immune pathologies.

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

“…Here we show for the first time, using two experimental approaches, that abundant IL-10 is spontaneously produced by Treg cells in tumors subcutaneously IL-10 is a crucial cytokine for immune suppression in tumors. Tumor-associated macrophages constitutively express IL-10 [34], thus maintaining an impaired immune status. We and others [35,36] have reported that IL-10 receptor blockade, when combined with TLR agonists and/or other immunostimulatory agents, rescue the functional paralysis of tumor-infiltrating DCs and macrophages toward an efficient cancer therapy.…”

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

“…In contrast to IL-6 that is ubiquitously expressed, IL-10 is mainly produced by macrophages and activated T cells. 17 Indeed, depletion of Kupffer cells (liver macrophages) has been shown to abolish induction of IL-10 expression in the regenerating liver after PHx. 21 Taken together, these findings suggest that after PHx, elevated levels of LPS in the liver stimulate Kupffer cells via targeting TLR4 to produce IL-10 that subsequently inhibits inflammatory response and liver regeneration.…”

“…17 IL-10 exerts its function via binding IL-10R1 and IL-10R2, followed by activation of STAT3 in myeloid cells. Conditional deletion of STAT3 in myeloid cells results in enhanced inflammatory response and inflammation in various organs including the liver.…”

“…However, how these inflammatory responses are controlled during liver regeneration remains largely unknown. In the current study, we have identified IL-10, a potent anti-inflammatory cytokine, 17 as an important regulator to suppress liver inflammation and regeneration after PHx via regulating production of proinflammatory cytokines and subsequently suppressing STAT3 activation in the liver.…”

BAC talk about cell type-specific regulation of human IL-10

“…Nonetheless, it is still possible that one or more regulatory elements necessary for hIL-10 expression lie outside of the BAC transgene or that one or more of the multitude of transcription factors shown to regulate IL-10 expression in the mouse, including STAT3, STAT4, AP-1, CREB, and cMAf (reviewed in ref. 17), might bind suboptimally to the appropriate sites in the transgene. The latter possibility seems especially relevant in light of recent studies by Saraiva et al (18), demonstrating that IL-10 production by Th1 cells requires high and sustained levels of antigen and IL-12, suggesting that the development of these regulatory cells is tightly controlled.…”