Type I IFN dependent and independent mechanisms of gene regulation: Implications in autoimmunity and drug metabolism.

摘要

The innate immune system is a complex system that is required for proper defense against bacterial and viral infections. A major component of the mammalian innate immune response is the Toll-like Receptor (TLR) family. Composed of 11 known TLRs, these receptors recognize pathogen-associated molecular patterns (PAMPs), conserved chemical structures found in bacteria, virus, fungus, other foreign pathogens, as well as endogenous ligands. Initial work in our lab identified distinct gene regulation patterns for each TLR. One distinct gene regulation pattern that was identified by our lab and others as being critical to anti-viral responses was the induction of type I interferons (Type I IFNs) and Type I IFN-related genes through the coordinate activation of the transcription factors NF-kappaB and IRF3. Interestingly, we also observed that activation of these transcription factors also results in biologically relevant gene repression programs. Induction of Type I IFNs by NF-kappaB and IRF3 results in repression of TGF-beta, which TLRs such as TLR9 use to promote cell proliferation through induction of TGF-beta target genes such as PDGF-B. In macrophages, where TLR3, but not TLR9, induces Type I IFNs, this mechanism of gene repression prevents TLR3 from inducing PDGF-B. Additionally, elucidation of this mechanism provides insight into how TLR9 can promote glomerulonephritis, a kidney disorder in lupus patients that is mediated by PDGF-BB and other factors. In addition to Type I IFN dependent mechanisms of gene repression, innate immune responses can also mediate Type I IFN independent mechanisms of gene repression. The Tontonoz laboratory first identified that activation of IRF3 is capable of repressing LXR target genes independent of Type I IFNs. Further studies in our lab indicated that this occurs through the transcriptional repression of LXR's heterodimeric transcriptional partner, RXRalpha. Additionally, repression of RXRalpha results in a repression of the target genes of other nuclear hormone receptors. We demonstrated that this has a significant impact on drug metabolism, identifying a mechanism by which viral infections contribute to the pathogenesis of Reye's Syndrome, a hepatotoxicity disorder that arises from aspirin therapy in the context of viral infections. Collectively, these findings demonstrate that the innate immune response involves crosstalk between a number of different signaling pathways and transcription factor families. Furthermore, improper activation or inhibition of these crosstalk mechanisms can have significant biological impact on a number of diseases, such as glomerulonephritis, Reye's Syndrome and possibly others.