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TLR3 TLR2 Signaling and Inhibits Signaling by Myd88 Adaptor-Like Is MyD88 Adaptor-Like Is Not Essential for TLR2 Signaling and Inhibits Signaling by TLR3 This information is current as Elaine F. Kenny, Suzanne Talbot, Mei Gong, Douglas T. of September 24, 2021. Golenbock, Clare E. Bryant and Luke A. J. O'Neill J Immunol 2009; 183:3642-3651; Prepublished online 28 August 2009; doi: 10.4049/jimmunol.0901140 http://www.jimmunol.org/content/183/6/3642 Downloaded from References This article cites 34 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/183/6/3642.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology MyD88 Adaptor-Like Is Not Essential for TLR2 Signaling and Inhibits Signaling by TLR31 Elaine F. Kenny,* Suzanne Talbot,† Mei Gong,‡ Douglas T. Golenbock,‡ Clare E. Bryant,† and Luke A. J. O’Neill2* Although a clear role for the adaptor protein myeloid differentiation factor-88 (MyD88) adaptor-like (Mal, or TIRAP) in TLR4 signaling has been demonstrated, there is limited information on its role in TLR2 signaling. Here we have systematically analyzed the role of Mal in signaling by TLR2, TLR4, and as a control TLR3 in murine macrophages and dendritic cells. Mal was not ␬ required for the induction of IL-6 or NF B activation at high concentrations of the TLR1/2 ligand Pam3Cys-Ser-(Lys)4 or the TLR2/6 ligand macrophage-activating lipopeptide-2 and was required for these responses only at low ligand concentrations. Similarly, induction of IL-6 by Salmonella typhimurium, which is sensed by TLR2, required Mal only at low levels of bacteria. Mal was required for IL-6 induction at all concentrations of the TLR4 ligand LPS. Mal deficiency boosted IL-6 induction by the TLR3 Downloaded from ligand polyinosinic-polycytidylic acid. Activation of JNK, but not p38 or I␬B degradation, was similarly potentiated in re- sponse to polyinosinic-polycytidylic acid in Mal-deficient macrophages. MyD88 was vital for all TLR2 and TLR4 responses and, similar to Mal, was also inhibitory for TLR3-dependent IL-6 and JNK induction. MyD88 interacted with the Toll/IL-1R domains of TLR1, TLR2, TLR4, and TLR6. Mal interacted with the Toll/Il-1R domains of TLR1, TLR2, and TLR4 but not with TLR6. Our study, therefore, reveals that Mal is dispensable in TLR2 signaling at high ligand concentrations in macrophages and dendritic cells, with MyD88 probably coupling to the TLR2 receptor complex at sufficient levels to allow activation. An inhibitory http://www.jimmunol.org/ role for Mal in TLR3 signaling to JNK was also demonstrated. The Journal of Immunology, 2009, 183: 3642–3651. he TLRs are a family of transmembrane glycoproteins own TIR domains, activates signaling cascades resulting in the that activate the innate immune response and act as a first recruitment of the IL-1R-associated kinases (IRAK) and ultimately T line of host defense (1, 2). There have been 10 human and the activation of transcription factors such as NF␬B and IFN-reg- 13 mouse TLRs characterized to date, all of which contain leucine- ulatory factor 3 (IRF3). The final products of TLR activation are rich repeats (3). The leucine-rich repeats are sufficiently flexible to cytokines, chemokines, and other inflammatory molecules (6, 7). allow for the binding of such diverse ligands as lipopeptides which The role of these adaptors has been clarified through the gen- by guest on September 24, 2021 bind TLR2, viral dsRNA which binds TLR3, and LPS which with eration of knockout mice. Mice lacking MyD88 demonstrate its MD2 binds TLR4 (4). Signaling is initiated by the binding of var- central role in response to all TLR ligands tested, with the excep- 3 ious adaptor proteins to the Toll/IL-1R (TIR) domain of the tion of TLR3 (8). MyD88 is also not required for the activation of TLRs. Four activating adaptors have been identified: myeloid dif- IRF3 by TLR4 which proceeds via the TRIF/TRAM pathway (4, ferentiation factor-88 (MyD88); MyD88 adaptor-like (Mal); TIR 6). Studies into the role of Mal in TLR signaling firstly revealed its ␤ domain-containing adaptor-inducing IFN- (TRIF); and TRIF-re- function in response to TLR4 activation (9, 10). Mice lacking the lated adaptor molecule (TRAM) (5). Their binding, through their TIR domain of Mal or the entire gene coding for Mal were then generated. It was established that Mal was required for TLR2 and TLR4 signaling only, and Mal was postulated to act as a bridging *School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ire- adaptor for MyD88 (11, 12). Subsequent to the identification of the land; †Centre for Veterinary Science, Department of Veterinary Medicine, Uni- versity of Cambridge, Cambridge, United Kingdom; and ‡Department of Infec- requirement of Mal in TLR2 signaling the generation of TLR1-, tious Diseases and Immunology, University of Massachusetts; Medical School, TLR2-, and TLR6-deficient mice revealed that TLR2 must het- Worcester, MA 01605 erodimerize with either TLR1 or TLR6 to recognize tri- and di- Received for publication April 8, 2009. Accepted for publication July 19, 2009. acylated lipopeptides, respectively (13–15). The costs of publication of this article were defrayed in part by the payment of page Further work into TLR4 signaling revealed the role of TRIF and charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. TRAM in activating the MyD88-independent signal cascade lead- 1 This work was supported by the Irish Research Council for Science, Engineering ing to IRF3 activation (16). Studies into mice lacking TRIF dem- and Technology, Science Foundation Ireland and by grants (to C.E.B.) from the Bio- onstrated that it was the sole adaptor required for TLR3 signaling technology and Biological Sciences Research Council and the Royal Society. (17). Recently, a novel inhibitory role for MyD88 in TLR3 sig- 2 Address correspondence and reprint requests to Prof. Luke A. J. O’Neill, School of naling has been discovered in which MyD88 prevents the overac- Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland. E-mail address: [email protected] tivation of the TRIF pathway upon TLR3 stimulation by inhibiting 3 Abbreviations used in this paper: TIR, Toll/IL-1R; BMDC, bone marrow-derived den- JNK phosphorylation (18). dritic cell; BMDM, bone marrow-derived macrophage; HEK-293T, human embryonic Although a clear role for Mal in TLR4 signaling has been dem- kidney T cell; IRAK, IL-1R-associated kinase; Mal, MyD88 adaptor-like; MyD88, my- onstrated, there is more limited information regarding its role in eloid differentiation factor-88; TRIF, Toll/Il-1R domain-containing adaptor-inducing IFN-␤; TRAM, TRIF-related adaptor molecule; IRF3, IFN-regulatory factor 3; TLR2 signaling. It has been previously demonstrated that Mal can Pam3CSK4, Pam3Cys-Ser-(Lys)4; Malp-2, macrophage-activating lipopeptide-2; MOI, bind TLR2 (12), but whether it can bind TLR1 or TLR6 has not multiplicity of infection; HA, hemagglutinin; poly(I:C), polyinosinic-polycytidylic acid. been examined. Further, whether Mal might be inhibitory toward Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 TLR3, in a similar manner to MyD88, has not been determined. www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901140 The Journal of Immunology 3643 Here, we have analyzed the role of Mal in the TLR2-, TLR3-, and (22 h). The supernatants were collected, and IL-6 production was measured TLR4-signaling pathways in macrophages and dendritic cells. We by ELISA. demonstrate that Mal has a greater role to play in TLR4 signaling Western blot analysis than in TLR2 signaling. Mal is not necessary for TLR2 signaling ϫ 5 at high ligand concentrations or in response to high levels of Sal- The immortalized BMDMs (8 10 cells/well of a 12-well plate) were stimulated the TLR ligands as outlined in the legends of Figs. 4 and 5. The monella typhimurium but is required for TLR4 signaling at all cells were washed twice in 1ϫ ice-cold PBS and lysed in 100 ␮loflow ligand concentrations tested. We have shown that TLR1, TLR2, stringency lysis buffer (50 mM HEPES (pH 7.5), 100 mM NaCl, 10% TLR4, and TLR6 all interact with MyD88 and that TLR1, TLR2, glycerol (v/v), 0.5% Nonidet P-40 (v/v), 1 mM EDTA, 1 mM sodium and TLR4 but not TLR6 interact with Mal. Finally, we have re- orthovanadate, 0.1 mM PMSF, 1 ␮g/ml aprotinin, and 1 ␮g/ml leupeptin). The cell lysates were centrifuged at 13,000 rpm for 10 min, supernatants vealed a greater inhibitory role for Mal in TLR3 signaling to JNK were collected, and the protein concentration of each was determined using and IL-6 induction when compared with MyD88. Thus, we pro- Coomassie Bradford reagent (Pierce) according to manufacturer’s instruc- pose that Mal is required for TLR4 signaling, is inhibitory in TLR3 tions.
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