title: MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists.
abstract: TLRs sense components of microorganisms and are critical host mediators of inflammation during infection. Different TLR agonists can profoundly alter inflammatory effects of one another, and studies suggest that the sequence of exposure to TLR agonists may importantly impact on responses during infection. We tested the hypothesis that synergy, priming, and tolerance between TLR agonists follow a pattern that can be predicted based on differential engagement of the MyD88-dependent (D) and the MyD88-independent (I) intracellular signaling pathways. Inflammatory effects of combinations of D and I pathway agonists were quantified in vivo and in vitro. Experiments used several D-specific agonists, an I-specific agonist (poly(I:C)), and LPS, which acts through both the D and I pathways. D-specific agonists included: peptidoglycan-associated lipoprotein, Pam3Cys, flagellin, and CpG DNA, which act through TLR2 (peptidoglycan-associated lipoprotein and Pam3Cys), TLR5, and TLR9, respectively. D and I agonists were markedly synergistic in inducing cytokine production in vivo in mice. All of the D-specific agonists were synergistic with poly(I:C) in vitro in inducing TNF and IL-6 production by mouse bone marrow-derived macrophages. Pretreatment of bone marrow-derived macrophages with poly(I:C) led to a primed response to subsequent D-specific agonists and vice versa, as indicated by increased cytokine production, and increased NF-kappaB translocation. Pretreatment with a D-specific agonist augmented LPS-induced IFN-beta production. All D-specific agonists induced tolerance to one another. Thus, under the conditions studied here, simultaneous and sequential activation of both the D and I pathways causes synergy and priming, respectively, and tolerance is induced by agonists that act through the same pathway.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Aranya
authors.initials: A
authors.lastname: Bagchi
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Herrup
authors.forename: H Shaw
authors.initials: HS
authors.lastname: Warren
authors.forename: James
authors.initials: J
authors.lastname: Trigilio
authors.forename: Hae-Sook
authors.initials: HS
authors.lastname: Shin
authors.forename: Catherine
authors.initials: C
authors.lastname: Valentine
authors.forename: Judith
authors.initials: J
authors.lastname: Hellman
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D051550:I-kappa B Kinase / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051193:Toll-Like Receptors; D016899:Interferon-beta; D051550:I-kappa B Kinase