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Receptor 5/Toll-Like Receptor 4 Complexes Involves Signaling Via Induction of Macrophage Nitric Oxide Production by Gram-Negative Flagellin Involves Signaling Via Heteromeric Toll-Like Receptor 5/Toll-Like Receptor 4 Complexes This information is current as of September 25, 2021. Steven B. Mizel, Anna N. Honko, Marlena A. Moors, Pameeka S. Smith and A. Phillip West J Immunol 2003; 170:6217-6223; ; doi: 10.4049/jimmunol.170.12.6217 http://www.jimmunol.org/content/170/12/6217 Downloaded from References This article cites 50 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/170/12/6217.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 25, 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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Induction of Macrophage Nitric Oxide Production by Gram-Negative Flagellin Involves Signaling Via Heteromeric Toll-Like Receptor 5/Toll-Like Receptor 4 Complexes1 Steven B. Mizel,2 Anna N. Honko, Marlena A. Moors, Pameeka S. Smith, and A. Phillip West The induction of cytokine synthesis by flagellin is mediated by a Toll-like receptor 5 (TLR5) signaling pathway. Although flagellin activation of the IL-1R-associated kinase and induction of TNF-␣ synthesis are dependent on TLR5 and not TLR4, we have found that flagellin stimulates NO in macrophages via a pathway that requires TLR5 and TLR4. Flagellin induced NO synthesis in HeNC2 cells, a murine macrophage cell line that expresses wild-type TLR4, but not in TLR4-mutant or -deficient GG2EE and 10ScNCr/23 cells. Flagellin stimulated an increase in inducible NO synthase (iNOS) mRNA and activation of the iNOS promoter. TLR5 forms heteromeric complexes with TLR4 as well as homomeric complexes. IFN-␥ permitted GG2EE and 10ScNCr/23 cells Downloaded from to produce NO in response to flagellin. Flagellin stimulated IFN-␤ synthesis and Stat1 activation. The effect of flagellin on iNOS gene expression was inhibited by a Stat1 mutant protein. Taken together, these results support the conclusions that flagellin induces distinct patterns of inflammatory mediators depending on the nature of the TLR5 signaling complex and that the induction of NO by flagellin involves signaling via TLR5/TLR4 complexes. The Journal of Immunology, 2003, 170: 6217–6223. nnate immunity serves as an essential first-line defense a variety of TLR5-positive cell types, including monocytes, fibro- http://www.jimmunol.org/ against microbial pathogens and may also influence the na- blasts, and epithelial cells to produce cytokines such as TNF-␣, I ture of the subsequent adaptive immune response (1–3). The IL-1, and IL-8 (3, 10, 11, 13–19) and NO in monocytes (13). accumulated evidence indicates that host cells involved in the in- Although inducers such as LPS and flagellin have been linked nate immune response use the members of a relatively small fam- with individual TLRs, there is mounting evidence that different ily of structurally related membrane proteins termed Toll-like re- TLRs may interact to produce distinct signaling events. For ex- ceptors (TLR)3 to recognize and respond to products from diverse ample, the activation of NF-␬B-dependent gene expression in groups of bacterial, viral, and fungal pathogens. Signaling via CHO cells and the induction of TNF-␣ in murine macrophages in TLRs results in the production of an array of proinflammatory response to Gram-positive bacterial peptidoglycan are dependent mediators, including cytokines (for example, IL-1, IL-8, and TNF- on the coexpression and physical interaction of TLR2 and TLR6 by guest on September 25, 2021 ␣), NO, leukotrienes, and platelet-activating factor. Presently, 10 (20). Although the expression of TLR2 is sufficient for a response human and nine murine TLRs have been identified that are char- to phenol-soluble modulin from Staphylococcus epidermidis, the acterized by the presence of a leucine-rich extracellular domain magnitude of the response is enhanced in the presence of TLR6 and cytoplasmic regions termed Toll/IL-1R homology (TIR) do- (21). In a prior study (13), we found that flagellin stimulated IRAK mains (see Ref. 4 for a review). Although TLRs do not, as a rule, activation and TNF-␣ production by GG2EE cells, a C3H/HeJ exhibit specificity for a single microbial product, they are individ- mouse-derived macrophage cell line (22) that expresses a mutant ually responsive to a limited group of molecules. For example, form of TLR4. These observations indicate that at least one form LPS (5–7), heat shock protein 60 (8), and Escherichia coli P fim- of flagellin signaling is not dependent on the expression of a wild- briae (9) signal via TLR4. type form of TLR4. However, as will be detailed in this report, the The results of several recent studies demonstrate that flagellin production of NO in response to flagellin is dependent on the co- from Gram-negative bacteria signals via TLR5 (10–12). As with expression and interaction of wild-type forms of TLR5 and TLR4. other TLRs, flagellin signaling via TLR5 results in activation of the IL-1R-associated kinase (IRAK) (12, 13). Flagellin stimulates Materials and Methods Cells and reagents Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157 The C3H/HeN-derived macrophage cell line HeNC2 and the LPS-hypore- sponsive C3H/HeJ-derived macrophage cell line GG2EE were maintained Received for publication February 7, 2003. Accepted for publication April 7, 2003. in RPMI 1640 containing 10% FBS and 20 ␮g/ml gentamicin. 10ScNCr/23 The costs of publication of this article were defrayed in part by the payment of page cells, a clonal derivative of primary C57BL/10ScNCr macrophages (23), charges. This article must therefore be hereby marked advertisement in accordance were provided by Dr. E. Lorenz. These cells do not express TLR4 mRNA with 18 U.S.C. Section 1734 solely to indicate this fact. or protein (5, 6). COS-1 cells and the murine macrophage cell line RAW 1 This work was supported by National Institutes of Health Grants AI38670 and 264.7 were maintained in DMEM with 10% FBS and gentamicin. Purified, AI51319 (to S. B. M.). endotoxin-free recombinant His-tagged Salmonella enteritidis flagellin was 2 Address correspondence and reprint requests to Dr. Steven B. Mizel, Department of prepared as previously described (16). As detailed in our prior studies Microbiology and Immunology, Wake Forest University School of Medicine, Medical (12–16), at the concentrations used in our studies the flagellin contained Center Boulevard, Winston-Salem, NC 27157. E-mail address: [email protected] insufficient residual LPS (usually Ͻ1 ng/ml) to produce a significant TLR4-dependent response (also see Fig. 1). Recombinant murine IFN-␥ 3 Abbreviations used in this paper: TLR, Toll-like receptor; HI, hemagglutinin; iNOS, inducible NO synthase; IRAK, IL-1R-associated kinase; IRF-3, IFN regulatory fac- was obtained from Life Technologies (Gaithersburg, MD). Anti-FLAG Ab tor-3; Mal, MyD88 adapter-like protein; TIR, Toll/IL-1 receptor homology; TIRAP, was obtained from Sigma-Aldrich (St. Louis, MO), high affinity anti- TIR domain-containing adaptor protein; TRIF, TIR domain-containing adaptor-in- hemagglutinin (anti-HA) Ab was obtained from Roche (Indianapolis, IN), ducing IFN-␤. anti-phospho-Stat1 Ab was purchased from Zymed (San Francisco, CA), Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 6218 INTERACTION OF TLR5 AND TLR4 IN FLAGELLIN SIGNALING porter (24) and Renilla luciferase control plasmid with or without TLR expression plasmids. The Renilla luciferase control plasmid provided a means to control for differences in transfection efficiency. The cells were transfected using the FuGene 6 reagent (Roche). After resting the cells overnight, the cultures were incubated in the presence or the absence of flagellin or LPS for 6 h before harvesting the cells. Inducible NOS pro- moter-dependent and Renilla luciferase activities were measured using the Promega dual-luciferase reporter assay system according to the manufac- turer’s instructions. Western blots To assess the association of TLR5 with TLR4, COS-1 cells were tran- siently transfected with TLR5-HA, TLR5-HA and TLR5-FLAG, or TLR5-HA and TLR4-FLAG expression plasmids using the Effectene trans- fection reagent (Qiagen, Valencia, CA) as previously described (12). After FIGURE 1. Activation of the iNOS promoter by flagellin is TLR5 de- resting the cells for 48 h, cell lysates were prepared and incubated with pendent. A, RAW264.7 cells were transiently transfected with the anti-FLAG Ab and recombinant protein G-agarose (Invitrogen, San Diego, p3XFlag-CMV-14 vector (0) or TLR5-Flag (TLR5), rested overnight, and CA)for2hat4°C (12). The immunoprecipitates were washed, eluted in then incubated in the absence (0) or the presence of 10Ϫ9 M flagellin (F) sample buffer, and electrophoresed in a 7.5% SDS-PAGE, and the proteins or 100 ng/ml LPS (L) for 6 h. The cells were harvested and assessed for the were transferred to a polyvinylidene difluoride membrane. The membrane level of inducible luciferase activity. The values have been normalized was then probed for TLR5-HA using the anti-HA high affinity Ab. The blot using the constitutive Renilla luciferase activity in each sample.
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