Interferon regulatory factor 5–Nuclear factor kappa-light-chain-enhancer of activated B cells p65 complex (IRF5–NF-κB p65 complex)

The IRF5–NF-κB p65 complex is a transcriptional assembly formed by the interaction of Interferon Regulatory Factor 5 (IRF5) and the p65 (RelA) subunit of the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) family. This complex plays a pivotal role in the innate immune system by co-regulating the expression of a specific subset of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-12, particularly in macrophages and dendritic cells [1, 5]. In the nucleus, the interaction between IRF5 and p65 is required for the efficient recruitment of these factors to the promoters of inflammatory genes, thereby driving the polarization of macrophages toward a pro-inflammatory M1 phenotype [1, 10]. Dysregulation or chronic activation of the IRF5–NF-κB p65 complex is strongly associated with the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and inflammatory bowel disease [2, 13]. Because this complex regulates a specific inflammatory 'cistrome,' it has emerged as an attractive therapeutic target [5, 16]. Disrupting the protein-protein interaction between IRF5 and p65 offers a more selective approach to treating chronic inflammation compared to broad NF-κB inhibition, potentially reducing off-target effects and preserving homeostatic immune functions [4, 16]. Experimental strategies to target this complex include the use of decoy peptides and small molecules designed to interfere with the IRF5-p65 binding interface [2, 7].

Other names

IRF5–RelA complexIRF5:RelA complexIRF5:p65 complexIRF5–NF-kappaB p65 complexIRF5–RELA complex

Inhibition of the protein-protein interaction between IRF5 and the NF-κB p65 subunit to prevent the formation of a functional transcriptional complex, thereby suppressing the expression of pro-inflammatory genes.