Regulation of interleukin-10 gene expression in macrophages engulfing apoptotic cells

Abstract

Apoptosis and the rapid clearance of apoptotic cells (ACs) by professional or nonprofessional phagocytes are normal and coordinated processes that ensure controlled cell growth and stress response with nonpathological outcomes. Uptake of ACs by phagocytes is thought to suppress autoimmune responses through the release of anti-inflammatory cytokines such as interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and inhibition of proinflammatory cytokines. The production of pro- and anti-inflammatory cytokines by phagocytes is highly regulated as part of an intrinsic mechanism to prevent inflammatory and autoimmune reactions in a physiological state. Production of IL-10 by phagocytes during clearance of ACs is critical to ensuring cellular homeostasis and suppression of autoimmunity. The molecular mechanism whereby IL-10 production is induced by ACs is only beginning to be understood. This review summarizes our recent work in this aspect of an essential physiological and homeostatic process.

FIG. 1.

Model of regulation of interleukin-10 (IL-10) production in response to apoptotic cells (ACs). ACs, through not clearly defined AC-associated molecular pattern (ACAMP) interacting with phagocytic receptors, induce IL-10 production by macrophages. One of the phagocytic receptors is CD36, the engagement of which by ACs induces p38 MAPK phosphorylation and the activation of a yet to be identified protein tyrosine kinase (X). Activation of p38 MAPK leads to the assembly of a Hox complex, composed of Pbx-1b, Prep-1, and Meis1 as a minimum, on the IL-10 promoter via the apoptotic cell response element (ACRE) at −105/−100. Prep-1 tyrosine phosphorylation is presumably carried out by the hypothetical kinase X. The Hox complex is the main transcriptional factor driving IL-10 expression in response to ACs and it does not appear to be variable in human individuals. Two negative regulatory elements (NREs) exist: NRE1 at −592 and NRE2 at −1082, which also represent 2 major SNPs in human populations. Both NREs interact with PARP-1, which acts as a transcription repressor, but the modes of action are different. NRE1 does not bind PARP-1 in resting macrophages and the interaction with the 24-kDa cleaved fragment of PARP-1 is induced by ACs being ingested by the phagocyte. NRE2 binds the intact, 113-kDa PARP-1 in resting cells and the binding is reduced in macrophages in contact with ACs, resulting in inhibition of IL-10 transcription. It is possible that the cleavage product of PARP-1 is actually a transcriptional activator for IL-10, opposing the effect of its precursor. This possibility awaits formal confirmation. Both NREs regulate IL-10 transcription in an allele-specific manner, resulting in variable levels of IL-10 gene expression in different individuals in response to ACs. Note that p38 activation is also inducible via the TLR pathway by microbial pathogens, which represents an evolutionarily independent route to induce IL-10 production. This pathway leads to the binding of transcription factors such as Sp1 to the IL-10 promoter region. Abbreviations: CM, cell membrane; NM, nuclear membrane; TATA, TATA box; Y-kinase, tyrosine kinase; ACRE, apoptotic cell response element; NRE, negative regulatory element. Solid lines represent proven relationship while dashed lines designate hypothetical dependency.