Biology and therapeutic potential of interleukin-10

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.

Figure 1.

IL-10 production is metabolically regulated. (A) Macrophages stimulated via TLR4 undergo a metabolic reprogramming toward glycolysis, which leads to the production of lactate and also to a break of the TCA cycle. As a result, succinate accumulates and activates HIF-1α, and the transcription of the Il1b gene is enhanced. Inhibition of this reprogramming, via the metabolic regulator PKM2 or during infection with M. tuberculosis, inhibits Il1b gene transcription, while promoting that of Il10. An increase of IL-10 production as a result of enhanced fatty acid metabolism has also been described, and is mediated by the transcription factor PBX1. In DCs, the maintenance of the pyruvate flux downstream of zymosan stimulation has been shown to reinforce the presence of acetylated histone 3 at the Il10 gene promoter, thus favoring IL-10 production. Other metabolic regulators, such as AMPK and mTOR, and metabolites, such as ATP, lactate, or butyrate, also contribute to IL-10 production by DCs, in different settings, but the molecular mechanisms in place remain largely unknown. (B) Gut microbiota derived short chain fatty acids signal through GPR43 and activate STAT3 and mTOR in differentiated Th1 cells, up-regulating the expression of Blimp-1 and consequently that of IL-10. In IL-27–induced Tr1 cells, IL-27R signaling induces the oxysterol 25-hydroxycholesterol (25-OHC). 25-OHC activates liver X receptor (LXR) and presumably decreases the expression of the transcription factor Blimp-1, thus limiting the expression of the Il10 gene. In IL-27–differentiated Tr1 cells, extracellular ATP (eATP) has been shown to increase the amounts of HIF-1α and consequently reduce those of AhR. This stabilization of HIF-1α also occurs under hypoxic conditions. Given the role of AhR in enhancing IL-10 expression in Tr1 cells, HIF-1α stabilization ultimately decreases IL-10 production. The Th1 switching from IFN-γ single-producing cells, to IFN-γ/IL-10 double-producing ones, and eventually IL-10 single-producing cells, is coupled to the biosynthesis of cholesterol, via cMaf. In Th17 cells, a short chain fatty acid, pentanoate, has been suggested to inhibit AMPK activation, thus releasing the mTOR pathway, increasing the glycolytic flux, and leading to the production of IL-10. In parallel, through an epigenetic-mediated mechanism, pentanoate reduces IL-17A expression.

Figure 2.

The anti-inflammatory response initiated downstream of the IL-10R. Binding of IL-10 to its receptor activates a major JAK1-TYK2-STAT3 signaling cascade, which culminates with the induction of the STAT3-mediated anti-inflammatory response. The STAT3 transcriptional reprogramming results in a number of molecules that include transcriptional repressors, chromatin modifiers, and post-transcriptional or post-translational regulators. Together, these molecules will limit the inflammatory response induced for example downstream of PRR activation. Recently, IL-10 has been shown to modulate the transcription of several metabolic regulators, including DDIT4, in a STAT3-dependent way. As DDIT4 is a regulator of mTORC, the IL-10R signaling limits the glycolytic flux downstream of TLR4 activation, which in turn controls the inflammatory response of the macrophage. In addition to the JAK-STAT3 pathway, STAT1, STAT5, and the PI3K-Akt cascade have also been reported to mediate IL-10 responses. The metabolic regulator AMPK has been reported to activate the PI3K-Akt-mTORC cascade, but also STAT3, in response to IL-10. STAT3 is moreover activated downstream of receptors for other IL-10 family cytokines, IL-6, and a number of other cytokines and growth factors. How the cell distinguishes the anti- from the pro-inflammatory reprogramming downstream of STAT3 activation is not fully understood, but the IL-10–induced SOCS3 has been reported to play an important role by blocking STAT3 at least downstream of the IL-6R, but not of the IL-10R. DUSP, dual-specifity phosphatase; Gsk3β, glycogen synthase kinase 3β; Sbno2, protein strawberry notch 2; TTP, tristetraprolin.

Figure 3.

Nonclassic roles of IL-10. The functions of IL-10 surpass its effects in immune cells. IL-10 plays an important role in the CNS, limiting the damage effects of neuroinflammation, but also contributing to several homeostatic processes. The molecular mechanisms operating in neurons or astrocytes in response to IL-10 remain elusive, but STAT3 and SOCS3 activation, as well as NF-κB, regulation have been proposed. Bone marrow–derived IL-10 activates the IL-10R/STAT3 signaling cascade, altering the chromatin landscape and the transcription factor occupancy at regulatory regions of thermogenic genes. The thermogenic gene expression is thus repressed and the energy expenditure limited. As a result, mice lacking IL-10 are protected against diet-induced obesity. In epithelial cells, IL-10 has been recently associated with wound healing. This is particularly important in intestinal epithelial cells (IECs), where the underlying mechanisms are starting to be unveiled. In response to IFN-γ, the enzyme 2,3-dioxygenase 1 (IDO1) catalyses the conversion of tryptophan (Trp) to kynurenine (Kyn), which activates the AhR, thus inducing the transcription of the IL-10Rα subunit. Activation of the IL-10R in response to macrophage-derived IL-10 leads to the STAT3-dependent CREB activation and the transcription of WSP-1, a promoter of epithelial cell proliferation and repair.

Figure 4.

The potential of enhancing IL-10 to treat disease. Several IL-10 enhancing strategies have been tried in a number of diseases and models of disease. The best understood effects of IL-10 at the mechanistic level have been described in the case of IBD and cancer. Side effects of IL-10 administration have been reported in both patients and healthy volunteers, but the underlying mechanisms remain unknown. The human figure represents clinical data, and the mouse figure preclinical findings. HCV, hepatitis C virus.