Gene silencing in severe systemic inflammation

Abstract

This critical care perspective appraises reprogramming of gene expression in inflammatory diseases as an emerging concept of clinical importance. We emphasize gene reprogramming that "silences" acute proinflammatory genes during severe systemic inflammation, wherein in the systemic inflammatory response syndrome (SIRS) exists as a continuum during severe sepsis, septic shock, and the multiorgan dysfunction and failure phenotypes without infection. In contrast, silencing of acute proinflammatory genes is not apparent in sites of localized inflammatory processes like rheumatoid arthritis. We discuss in three parts the clinical context and the translational basic science associated with gene silencing during the SIRS continuum of severe systemic inflammation: (1) reprogramming of acute proinflammatory genes; (2) a "nuclear factor-kappaB paradox," coupled with RelB expression, that combine to silence genes using an epigenetic (inherited and reversible) signature on the nucleosome; and (3) the potential clinical importance of compartmentalization in gene silencing. Our emergent understanding of these physiologic processes may provide a novel framework for developing treatments.

Figure 1.

Reprogramming of expression of clinically important genes and gene products during inflammatory shock. This simplified scheme shows three functional and clinically significant gene expression patterns typical of inflammatory shock: (1) increased expression followed by sustained silencing of acute proinflammatory genes (solid line), such as IL-1β and tumor necrosis factor-α; (2) sustained increases in expression of antiinflammatory genes (dotted line), such as IL-1 receptor antagonist and IL-6; and (3) sustained increases in expression of “late” proinflammatory genes (dashed line), such as high mobility group 1B (HMGB1) and macrophage inhibiting factor (MIF). Changes in expression of many other genes or gene products (with increases or decreases) occur within or in addition to these signatures.

Figure 2.

Nuclear mechanisms contributing to silencing of acute proinflammatory genes. The silenced phenotype for acute proinflammatory gene expression during inflammatory shock is associated with the following: (1) disrupted promoter assembly of nuclear factor (NF)-κB p65:p50 transcriptionally active heterodimers; (2) induction of an epigenetic “chromatin silencing mark” that involves sustained nucleosomal histone 3 (H3) lysine 9 methylation (K9-meth) and reduced H3 serine 10 phosphorylation (S10-Phos); and (3) increases in nuclear RelB, which limit NF-κB p65 transactivation by binding to NF-κB in nucleoplasm and/or through binding directly to promoter complexes of proteins and DNA. K9-demeth = H3 lysine 9 demethylation; S10-dephos = H3 serine 10 dephosphorylation.