Citation/Abstract

Monocytes and macrophages respond to bacterial components as a part of the innate immune response to fight off pathogenic infections. Various biologically active cytokines are produced to mediate the inflammatory process and stimulate a cascade of inflammatory mediators. A microenvironment is maintained to activate cells, clear pathogens, and contain the area of infection. We examine specifically two pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). The inappropriate or excessive production of these cytokines results in tissue damage and has implications in chronic inflammation and autoimmune diseases. TNF-α potently stimulates the production of other cytokines and adhesion molecules. It recruits other inflammatory cells and upregulates the adaptive immune response. We explore how TNF-α production is regulated by two mechanisms. We find that chromatin structures in the promoter region of the TNF-α gene are altered with maturation. In vitro human monocytic cell lines representing different stages of maturation demonstrate increasing histone H3 acetylation with increasing maturation. Primary human monocytes and macrophages also show similar phenomena. Increasing acetylation of histone H3 is associated with increasing responsiveness to stimulation. Another aspect of TNF-α gene regulation is examined from the perspective of signaling pathways initiated by IFN-γ and lipopolysaccharide (LPS). We investigate how IFN-γ may be able to potentiate the LPS-inducible TNF-α production in monocytes and determine that this occurred at the level of transcription. We also assess the role of IFN-γ in pathogenesis of the autoimmune disease, systemic lupus erythematosus. Specifically, a dinucleotide repeat polymorphism in the first intron of the human IFN-γ gene is associated with specific disease manifestations. Understanding how cytokines in the inflammatory process are regulated has important clinical significance. Controlling the aberrant production of these cytokines may be used therapeutically to prevent chronic inflammation and autoimmune conditions.