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Divisions of Pediatric
*
Critical Care and
Infectious Diseases, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California School of Medicine, Los Angeles, CA 90048
Toll-like receptor 2 (TLR2) and TLR4 play important roles in innate
immune responses to various microbial agents. We have previously shown
that human dermal endothelial cells (HMEC) express TLR4, but very
little TLR2, and respond to LPS, but not to Mycobacterium
tuberculosis 19-kDa lipoprotein, unless transfected with TLR2.
Here we report that HMEC are unresponsive to several additional
biologically relevant TLR2 ligands, including, phenol-soluble modulin
(PSM), a complex of three small secreted polypeptides from the skin
commensal Staphylococcus epidermidis, soluble
tuberculosis factor (STF), and Borrelia burgdorferi
outer surface protein A lipoprotein (OspA-L). Expression of TLR2
renders HMEC responsive to all these ligands. We further characterized
the signaling pathway in response to STF, OspA-L, and PSM in
TLR2-transfected HMEC. The TLR2 signaling pathway for NF-
B
trans-activation shares the IL-1R signaling molecules.
Dominant negative constructs of TLR2 or TLR6 inhibit the responses of
STF and OspA-L as well as PSM in TLR2-transfected HMEC, supporting the
concept of functional cooperation between TLR2 and TLR6 for all these
TLR2 ligands. Moreover, we show that Toll-interacting protein (Tollip)
coimmunoprecipitates with TLR2 and TLR4 using HEK 293 cells, and
overexpression of Tollip inhibits NF-B activation in response to
TLR2 and TLR4 signaling. Collectively, these findings suggest that
there is functional interaction between TLR2 and TLR6 in the cellular
response to STF and OspA-L in addition to S. epidermidis
(PSM) Ags, and that engagement of TLR2 triggers a signaling cascade,
which shares the IL-1R signaling molecules, similar to the TLR4-LPS
signaling cascade. Our data also suggest that Tollip may be an
important constituent of both the TLR2 and TLR4 signaling
pathways.
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V. J. Quesniaux, D. M. Nicolle, D. Torres, L. Kremer, Y. Guerardel, J. Nigou, G. Puzo, F. Erard, and B. Ryffel Toll-Like Receptor 2 (TLR2)-Dependent-Positive and TLR2-Independent-Negative Regulation of Proinflammatory Cytokines by Mycobacterial Lipomannans J. Immunol., April 1, 2004; 172(7): 4425 - 4434. [Abstract] [Full Text] [PDF]
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A. Hasebe, A. Yoshimura, T. Into, H. Kataoka, S. Tanaka, S. Arakawa, H. Ishikura, D. T. Golenbock, T. Sugaya, N. Tsuchida, et al. Biological Activities of Bacteroides forsythus Lipoproteins and Their Possible Pathological Roles in Periodontal Disease Infect. Immun., March 1, 2004; 72(3): 1318 - 1325. [Abstract] [Full Text] [PDF]
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J. Branger, J. C. Leemans, S. Florquin, S. Weijer, P. Speelman, and T. van der Poll Toll-like receptor 4 plays a protective role in pulmonary tuberculosis in mice Int. Immunol., March 1, 2004; 16(3): 509 - 516. [Abstract] [Full Text] [PDF]
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S. Totemeyer, N. Foster, P. Kaiser, D. J. Maskell, and C. E. Bryant Toll-Like Receptor Expression in C3H/HeN and C3H/HeJ Mice during Salmonella enterica Serovar Typhimurium Infection Infect. Immun., November 1, 2003; 71(11): 6653 - 6657. [Abstract] [Full Text] [PDF]
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K. Saito, T. Yajima, H. Nishimura, K. Aiba, R. Ishimitsu, T. Matsuguchi, T. Fushimi, Y. Ohshima, Y. Tsukamoto, and Y. Yoshikai Soluble Branched {beta}-(1,4)Glucans from Acetobacter Species Show Strong Activities to Induce Interleukin-12 in Vitro and Inhibit T-helper 2 Cellular Response with Immunoglobulin E Production in Vivo J. Biol. Chem., October 3, 2003; 278(40): 38571 - 38578. [Abstract] [Full Text] [PDF]
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A. J. Gehring, R. E. Rojas, D. H. Canaday, D. L. Lakey, C. V. Harding, and W. H. Boom The Mycobacterium tuberculosis 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Regulated HLA-DR and Fc{gamma}R1 on Human Macrophages through Toll-Like Receptor 2 Infect. Immun., August 1, 2003; 71(8): 4487 - 4497. [Abstract] [Full Text] [PDF]
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R. I. Tapping and P. S. Tobias Mycobacterial lipoarabinomannan mediates physical interactions between TLR1 and TLR2 to induce signaling Innate Immunity, August 1, 2003; 9(4): 264 - 268. [Abstract] [PDF]
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L.-Y. Huang, J. Aliberti, C. A. Leifer, D. M. Segal, A. Sher, D. T. Golenbock, and B. Golding Heat-Killed Brucella abortus Induces TNF and IL-12p40 by Distinct MyD88-Dependent Pathways: TNF, Unlike IL-12p40 Secretion, Is Toll-Like Receptor 2 Dependent J. Immunol., August 1, 2003; 171(3): 1441 - 1446. [Abstract] [Full Text] [PDF]
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A. Yoder, X. Wang, Y. Ma, M. T. Philipp, M. Heilbrun, J. H. Weis, C. J. Kirschning, R. M. Wooten, and J. J. Weis Tripalmitoyl-S-Glyceryl-Cysteine-Dependent OspA Vaccination of Toll-Like Receptor 2-Deficient Mice Results in Effective Protection from Borrelia burgdorferi Challenge Infect. Immun., July 1, 2003; 71(7): 3894 - 3900. [Abstract] [Full Text] [PDF]
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 G. Fenhalls, G. R. Squires, L. Stevens-Muller, J. Bezuidenhout, G. Amphlett, K. Duncan, and P. T. Lukey Associations between Toll-Like Receptors and Interleukin-4 in the Lungs of Patients with Tuberculosis Am. J. Respir. Cell Mol. Biol., July 1, 2003; 29(1): 28 - 38. [Abstract] [Full Text] [PDF]
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P.-Y. Bochud, T. R. Hawn, and A. Aderem Cutting Edge: A Toll-Like Receptor 2 Polymorphism That Is Associated with Lepromatous Leprosy Is Unable to Mediate Mycobacterial Signaling J. Immunol., April 1, 2003; 170(7): 3451 - 3454. [Abstract] [Full Text] [PDF]
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G. Melmed, L. S. Thomas, N. Lee, S. Y. Tesfay, K. Lukasek, K. S. Michelsen, Y. Zhou, B. Hu, M. Arditi, and M. T. Abreu Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut J. Immunol., February 1, 2003; 170(3): 1406 - 1415. [Abstract] [Full Text] [PDF]
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 R. Girard, T. Pedron, S. Uematsu, V. Balloy, M. Chignard, S. Akira, and R. Chaby Lipopolysaccharides from Legionella and Rhizobium stimulate mouse bone marrow granulocytes via Toll-like receptor 2 J. Cell Sci., January 15, 2003; 116(2): 293 - 302. [Abstract] [Full Text] [PDF]
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D. Schilling, K. Thomas, K. Nixdorff, S. N. Vogel, and M. J. Fenton Toll-Like Receptor 4 and Toll-IL-1 Receptor Domain-Containing Adapter Protein (TIRAP)/Myeloid Differentiation Protein 88 Adapter-Like (Mal) Contribute to Maximal IL-6 Expression in Macrophages J. Immunol., November 15, 2002; 169(10): 5874 - 5880. [Abstract] [Full Text] [PDF]
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R. Jacinto, T. Hartung, C. McCall, and L. Li Lipopolysaccharide- and Lipoteichoic Acid-Induced Tolerance and Cross-Tolerance: Distinct Alterations in IL-1 Receptor-Associated Kinase J. Immunol., June 15, 2002; 168(12): 6136 - 6141. [Abstract] [Full Text] [PDF]
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K. Ruckdeschel, O. Mannel, and P. Schrottner Divergence of Apoptosis-Inducing and Preventing Signals in Bacteria-Faced Macrophages Through Myeloid Differentiation Factor 88 and IL-1 Receptor-Associated Kinase Members J. Immunol., May 1, 2002; 168(9): 4601 - 4611. [Abstract] [Full Text] [PDF]
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R. van Crevel, T. H. M. Ottenhoff, and J. W. M. van der Meer Innate Immunity to Mycobacterium tuberculosis Clin. Microbiol. Rev., April 1, 2002; 15(2): 294 - 309. [Abstract] [Full Text] [PDF]
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R. N. Fichorova, A. O. Cronin, E. Lien, D. J. Anderson, and R. R. Ingalls Response to Neisseria gonorrhoeae by Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling J. Immunol., March 1, 2002; 168(5): 2424 - 2432. [Abstract] [Full Text] [PDF]
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Y. Bulut, E. Faure, L. Thomas, H. Karahashi, K. S. Michelsen, O. Equils, S. G. Morrison, R. P. Morrison, and M. Arditi Chlamydial Heat Shock Protein 60 Activates Macrophages and Endothelial Cells Through Toll-Like Receptor 4 and MD2 in a MyD88-Dependent Pathway J. Immunol., February 1, 2002; 168(3): 1435 - 1440. [Abstract] [Full Text] [PDF]
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G. Zhang and S. Ghosh Negative Regulation of Toll-like Receptor-mediated Signaling by Tollip J. Biol. Chem., February 22, 2002; 277(9): 7059 - 7065. [Abstract] [Full Text] [PDF]
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