Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Targeting IL-10 Family Cytokines for the Treatment of Human Diseases Xiaoting Wang,1 Kit Wong,2 Wenjun Ouyang,3 and Sascha Rutz4 1Department of Comparative Biology and Safety Sciences, Amgen, South San Francisco, California 94080 2Department of Biomarker Development, Genentech, South San Francisco, California 94080 3Department of Inflammation and Oncology, Amgen, South San Francisco, California 94080 4Department of Cancer Immunology, Genentech, South San Francisco, California 94080 Correspondence: [email protected]; [email protected] Members of the interleukin (IL)-10 family of cytokines play important roles in regulating immune responses during host defense but also in autoimmune disorders, inflammatory diseases, and cancer. Although IL-10 itself primarily acts on leukocytes and has potent immunosuppressive functions, other family members preferentially target nonimmune com- partments, such as tissue epithelial cells, where they elicit innate defense mechanisms to control viral, bacterial, and fungal infections, protect tissue integrity, and promote tissue repair and regeneration. As cytokines are prime drug targets, IL-10 family cytokines provide great opportunities for the treatment of autoimmune diseases, tissue damage, and cancer. Yet no therapy in this space has been approved to date. Here, we summarize the diverse biology of the IL-10 family as it relates to human disease and review past and current strategies and challenges to target IL-10 family cytokines for clinical use. nterleukin (IL)-10, a cytokine with pleiotropic kines (Fiorentino et al. 1989). It has since been Iimmunosuppressive functions, is also the found that IL-10 is expressed by a wide variety of founding member of the IL-10 family of cyto- cell types of both the innate and the adaptive kines (Fig. 1). In addition to IL-10 itself, this arms of the immune system, including macro- group of cytokines encompasses IL-19, IL-20, phages, monocytes, dendritic cells (DCs), mast IL-22, IL-24, and IL-26, which are collectively cells, eosinophils, neutrophils, natural killer referred to as the IL-20 subfamily, as well as the (NK) cells, CD4+ and CD8+ T cells, and B cells more distantly related members IL-28A, IL-28B, (Moore et al. 2001; Ouyang et al. 2011). IL-20 and IL-29, also known as the interferon (IFN)-λ subfamily cytokines are also produced mainly family or type III IFNs (Pestka et al. 2004; Ou- by immune cells, such as myeloid cells and lym- yang et al. 2011; Rutz et al. 2014). phocytes (Rutz et al. 2014). Myeloid cells are the IL-10 was initially described as a secreted primary source for IL-19, IL-20, and IL-24 cytokine synthesis inhibitory factor (CSIF) pro- (Wolk et al. 2002). Epithelial cells, the main tar- duced by T helper (Th)2 T-cell clones with the get cells of IL-20 family cytokines, also produce ability to inhibit the production of Th1 cyto- IL-19, IL-20, and IL-24 in response to cytokines Editors: Warren J. Leonard and Robert D. Schreiber Additional Perspectives on Cytokines available at www.cshperspectives.org Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028548 Cite this article as Cold Spring Harb Perspect Biol 2019;11:a028548 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press X. Wang et al. IL-22 IL-19 IL-28A IL-22BP IL-20 IL-20 IL-28B IL-10 IL-22 IL-24 IL-24 IL-26 IL-29 IL-22RA1 IL-22RA1 IL-10RB IL-20RB IL-10RB IL-20RA IL-20RB IL-20RA IL-10RA IL-28RA IL-10RB IL-10RB IL-10 IL-22 IL-20 receptor IL-20 receptor IL-26 IL-28 receptor receptor type 1 type 2 receptor receptor Figure 1. Interleukin (IL)-10 family cytokines and their receptors. secreted by immune cells (Hunt et al. 2006; Sa et uses IL-10RA, whereas IL-19, IL-20, and IL-24 al. 2007; Wolk et al. 2009b). T cells are a primary use IL-20RA as receptor α-subunits. IL-22 binds source for IL-22, IL-24, and IL-26. Additionally, IL-22RA1, which can also be bound by IL-20 IL-22 is produced by various other lymphoid and IL-24, collectively defining the IL-20 sub- populations, including γδ-T cells, NK cells, family. IL-28A, IL-28B, and IL-29, on the other and innate lymphoid cells (ILCs) (Rutz et al. hand, use a unique IL-28RA subunit. In addition 2013, 2014). Finally, both leukocytes and epithe- to these membrane-bound receptors, a soluble lial cells are major sources of IFN-λ family cy- form of the IL-22 receptor (IL-22BP or IL- tokines (Fig. 1) (Kotenko et al. 2003; Sheppard 22RA2) with homology to the extracellular do- et al. 2003; Uzé and Monneron 2007). main of IL-22RA1, binds IL-22 with high affinity Although the biological functions of the and blocks its activity (Ouyang et al. 2011; Rutz other IL-10 family cytokines are quite distinct et al. 2014). from IL-10 itself, all family members share sig- IL-10 family receptors signal through Janus nificant structural homology, having evolved tyrosine kinases (JAKs) and signal transducers through gene duplication. Most IL-10 family cy- and activators of transcription (STATs). Recep- tokines form homodimers, whereas some family tor α-subunits are constitutively associated with members, such as IL-22, exist in a monomeric Jak1, whereas Jak2 or Tyk2 are bound to the β- form. IL-10 family cytokines signal through het- subunits. Ligand binding initiates recruitment erodimeric receptors, composed of class II re- and phosphorylation of STATs, which in turn ceptor α- and β-subunits (Pestka et al. 2004). form homo- and heterodimers that translocate The prototypical class II receptor structure con- into the nucleus to induce transcription. IL-10 sists of tandem β–sheet-rich immunoglobulin and the IL-20 subfamily cytokines signal pri- (Ig)-like domains with fibronectin type III con- marily through STAT3 and STAT1, whereas nectivity. The α-receptor subunits show higher IL-28A, IL-28B, and IL-29 activate the ISGF3 affinity for the cytokine ligand than the β-sub- complex (Pestka et al. 2004; Ouyang et al. units. Interestingly, the receptor-binding mode 2011; Rutz et al. 2014). is virtually identical for monomeric or dimeric Distinct receptor expression patterns drive IL-10 family cytokines (Pestka et al. 2004). the diverse biology of IL-10 family cytokines The shared usage of common receptor sub- (Fig. 1). The IL-10RB β-subunit is ubiquitously units is a defining feature of the IL-10 cytokine expressed throughout the body, whereas expres- family (Fig. 1). All members bind either the IL- sion of the IL-20RB β-subunit is more restricted. 10RB or IL-20RB β-receptor subunits in combi- IL-10RA is mainly expressed on leukocytes. In nation with varying α-subunits. IL-10 uniquely contrast, IL-20 subfamily receptors showa rather 2 Cite this article as Cold Spring Harb Perspect Biol 2019;11:a028548 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Targeting IL-10 Family Cytokines to Treat Diseases restricted expression pattern. In particular the α- IL-10 also has stimulatory effects on CD8+ T receptor subunits, IL-20RA and IL-22RA1, are cells, and augments their proliferation and cyto- preferentially expressed on epithelial cells and toxic activity (Groux et al. 1998; Mumm et al. fibroblasts, but absent from hematopoietic cells 2011). It enhances the survival of human B cells (Aggarwal et al. 2001; Blumberg et al. 2001; Wolk and promotes B-cell proliferation (Levy and et al. 2002). IL-22RA1 is highly expressed in the Brouet 1994; Itoh and Hirohata 1995) and con- skin, pancreas, kidney, lung, intestine, and liver. tributes to the differentiation of B cells and their IL-20RA is expressed in the skin, lung, ovary, production and isotype switch of antibodies testes, and placenta, and at lower levels in the (Rousset et al. 1992). intestine and liver (Rutz et al. 2013, 2014). The Role of IL-10 in Inflammatory Bowel TARGETING IL-10 FOR THE TREATMENT Disease OF HUMAN AUTOIMMUNE DISEASES Given its multiple anti-inflammatory functions, As a major immune regulatory cytokine, IL-10 it is not surprising that IL-10 exerts essential can be produced by many leukocyte subsets and regulatory roles in many human autoimmune is under the control of various signal transduc- diseases. Inflammatory bowel disease (IBD) tion pathways and transcriptional networks comprises ulcerative colitis (UC) and Crohn’s (Saraiva and O’Garra 2010; Rutz and Ouyang disease (CD), both of which show uncontrolled 2011, 2016). According to the expression of its inflammation in the intestinal tract but differ in receptor, IL-10 acts on many cells of the immune pathophysiology. Mice deficient in either IL-10 system (Fig. 2), where it has profound anti-in- or the IL-10 receptor α or β chains develop flammatory functions (Moore et al. 2001; Rutz spontaneous colitis (Kühn et al. 1993), which is and Ouyang 2011). IL-10 mainly targets anti- dependent on the presence of the intestinal mi- gen-presenting cells (APCs), such as monocytes crobiota and involves the up-regulation of IL-23 and macrophages, and inhibits their release of (Sellon et al. 1998; Yen et al. 2006). Exogenously proinflammatory cytokines, such as tumor ne- provided recombinant IL-10 can delay and at- crosis factor α (TNF-α), IL-1β, IL-6, IL-8, gran- tenuate colitis development in these IL-10-de- ulocyte colony-stimulating factor (G-CSF), and ficient mice.