Regulation of NF-kappaB signaling pathways in immune and inflammatory responses.

摘要

The transcription factor, NF-kappaB, upregulates expression of genes involved in the immune and inflammatory responses. An understanding of the regulation of NF-kappaB is therefore essential in order to control or enhance these immune responses. Many inducers of NF-kappaB activity are known, however the signal transduction pathways leading to NF-kappaB activation are not fully characterized. This manuscript provides data which helps elucidate the control of NF-kappaB.; Because NF-kappaB regulates inflammatory responses, we thought that NF-kappaB may be inhibited by anti-inflammatory agents. The salicylates, a class of these agents, are plant-derived compounds which are known to inhibit prostaglandin synthesis. All of the effects of these drugs can not however be attributed to this inhibition. We demonstrate that sodium salicylate and aspirin inhibit the activation of NF-kappaB and its transcriptional activity. This inhibition is not due to non-specific interference of these drugs with our assays. Furthermore, the inhibition occurs at a step upstream of the release of NF-kappaB from its inhibitor, IkappaB. For the first time, therefore, we link the salicylates with the inhibition of an important inflammatory mediator in mammalian cells.; The IL-1 receptor and the Toll protein are receptors bearing a homologous cytosolic domain. Signal transduction pathways originating with these receptors are conserved from human to Drosophila and result in the activation of the transcription factors, NF-kappaB and AP-1, induction of host defense genes. The adapter protein, TRAF6, is involved in signal transduction in the Toll and IL-1 receptor signaling pathways. We have cloned a new member of this pathway, ECSIT (Evolutionarily Conserved Signaling Intermediate in Toll pathway), which we isolated by yeast two hybrid assay using TRAF6 as bait. ECSIT binds TRAF6 but does not interact with TRAF2 or TRAF5. A dominant negative deletion mutant of ECSIT, ECSITDelta, inhibits NF-kappaB activation by Toll suggesting that ECSIT participates in Toll signaling. ECSITDelta also inhibits NF-kappaB activation by IRAK, a conserved kinase of the Toll signaling pathway, but not by RIP, a kinase involved in NF-kappaB activation through the TNF receptors. ECSIT appears to activate NF-kappaB through the kinase, MEKK-1, since ECSIT binds MEKK-1, and ECSITDelta inhibits MEKK-1 activation of NF-kappaB. Furthermore, ECSIT promotes the proteolytic processing of MEKK-1 to its active form whereas ECSITDelta inhibits this processing. We have also cloned a Drosophila homolog of ECSIT, dECSIT, that activates transcription from the Drosophila diptericin promoter and induces transcription of the antibacterial peptides, attacin and defensin. ECSIT is therefore a conserved signaling intermediate in innate immune function.