Regulation of Interferon Regulatory Factors in LPS-Stimulated Macrophages

摘要

Macrophages secrete interferons (IFNs), as well as other inflammatory cytokines,following stimulation with lipopolysaccharide (LPS), the outer membrane component of Gram negative bacteria that has been implicated as the initiator of the sepsis-associated Systemic Inflammatory Response Syndrome (SIRS). The interferon regulatory factors (IRFs) comprise a family of DNA binding proteins that positively and negtively regulate transcription of IFN and certain IFN-inducible genes. Basal and LPS-inducible levels of mRNA expressed by three IRF family member genes, i.e., IRF-1, IRF-2, and ICSBP, as well as a panel of other well characterized, SIRS-associated, inflammatory genes, were analyzed in macrophages derived from fully LPS-responsive mouse strains (Lps(n)), genetically LPS-hyporesponsive (Lps(d)) mice, IRF-1 and IRF-2 'knockout' mice, as well as from Lpsn macrophages rendered 'endotoxin tolerant' in vitro. Our results suggest that the IRF nuclear binding proteins, as well as serine/threonine phosphatases, play important roles in LPS-induced gene expression and may provide novel targets for therapeutic intervention, not only in Gram negative sepsis, but also in other syndromes characterized by inflammatory mediator excess.