Interleukin-10: new perspectives on an old cytokine

Abstract

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.

Fig. 1. A schematic of mouse chromosome 1, showing the IL-10 gene and its neighbors

Arrows depict orientation of gene expression. The sizes of intervening sequences are designated below. Regulatory elements, such as insulators, enhancers, and silencers, are not shown.

Fig. 2. The IL-10 receptor and a simplified version of signaling from this receptor

The functional receptor complex is composed of two subunits each of IL-10 R1 and IL-10R2. The Janus tyrosine kinases JAK1 and Tyk2 associate with the cytoplasmic tails of the receptor and phosphorylate tyrosine residues in IL-10R1, to which STAT3 is recruited. STAT3 homodimers translocate into the nucleus and bind to STAT elements in several immune response genes, including IL-10 itself and the SOCS genes.

Fig. 3. A diagram of regulatory elements in the murine and human IL-10 promoters

The binding sites for transcription factors (circles and boxes) in the murine (top) and human (bottom) IL-10 promoter with numbering relative to the translation start site. For details on each transcription factor, please consult text.

Fig. 4. The production of cytokines from tumor-associated macrophages

The relative levels of mRNA for IL-10 (left) and TNF (right) from tumor-associated macrophages were determined by reverse transcriptase polymerase chain reaction and were compared with peritoneal macrophages from normal non-tumor-bearing mice. mRNA levels were determined 2 h after in vitro stimulation with LPS and are compared with unstimulated cells (0′).