Bjorkbacka, HarryFitzgerald, Katherine AHuet, FrancoisLi, XiaomanGregory, James A.Lee, MelindaOrdija, Christine M.Dowley, Nicole E.Golenbock, Douglas T.Freeman, Mason W.2022-08-232022-08-232004-09-162011-03-25Physiol Genomics. 2004 Nov 17;19(3):319-30. Epub 2004 Sep 14. <a href="http://dx.doi.org/10.1152/physiolgenomics.00128.2004">Link to article on publisher's site</a>1094-8341 (Linking)10.1152/physiolgenomics.00128.200415367722https://hdl.handle.net/20.500.14038/35262Myeloid differentiation protein-88 (MyD88) is a signal adaptor protein required for cytokine production following engagement of Toll-like receptors (TLRs) by their cognate ligands. Activation of both TLR-3 and TLR-4, however, can engage signaling events independent of MyD88 expression. The relative importance of these MyD88-dependent and -independent signaling pathways in the macrophage response to lipopolysaccharide (LPS) is unknown. Here we define these events using microarray expression profiling of LPS-stimulated macrophages taken from MyD88-null and wild-type mice. Of the 1,055 genes found to be LPS responsive, only 21.5% were dependent on MyD88 expression, with MyD88-independent genes constituting 74.7% of the genetic response. This MyD88-independent gene expression was predominantly transcriptionally regulated, as it was unaffected by cycloheximide blockade of new protein synthesis. A previously undescribed group of LPS-regulated genes (3.8%), whose induction or repression was significantly greater in the absence of MyD88, was also identified by these studies. The regulation of these genes suggested that MyD88 could serve as a molecular brake, constraining gene activity in a subset of LPS-responsive genes. The findings generated with LPS stimulation were recapitulated by exposure of macrophages to live Escherichia coli. These expression-profiling studies redefine the current dogma of TLR-4 signaling and establish that MyD88, although essential for some of the best-characterized macrophage responses to LPS, is not required for the regulation of the majority of genes engaged by macrophage exposure to endotoxin or live bacteria.en-USAdaptor Proteins, Signal TransducingAnimalsAntigens, DifferentiationCells, CulturedDNA-Binding ProteinsEscherichia coli K12Gene Expression ProfilingGene Expression RegulationGenetic MarkersHumansInflammationInterferon Regulatory Factor-3KidneyLipopolysaccharidesMacrophage ActivationMacrophagesMiceMice, Inbred C57BLMicroarray AnalysisMyeloid Differentiation Factor 88NF-kappa BProteinsReceptors, ImmunologicSignal TransductionToll-Like Receptor 4Transcription FactorsTransfectionImmunology and Infectious DiseaseJournal Articlehttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1094&amp;context=infdis_pp&amp;unstamped=1https://escholarship.umassmed.edu/infdis_pp/951901419infdis_pp/95