Correspondence

Toll Genes and Responsiveness to Bacterial Endotoxins

N Engl J Med 2000; 342:664-665March 2, 2000

Article

To the Editor:

The review of the toll-like receptors (TLRs) by Modlin et al. (June 10 issue)1 contained some important errors. The authors contend that TLR2 signals the presence of endotoxin, and thus alerts the host to invading gram-negative bacteria. This is wrong. TLR4 carries out this function. The genetic evidence is categorical. Animals lacking TLR4 do not respond to endotoxin and have increased susceptibility to overwhelming gram-negative sepsis.2 Animals without TLR2, in contrast, have a completely normal response to both endotoxin and gram-negative bacterial infection.3 These facts cannot be reconciled with the claim that TLR2 transmits the lipopolysaccharide signal. In addition, no reports of contact between the transcription factor MyD88 and TLR2 have appeared in the literature, and the interleukin-1 receptor–associated kinase (IRAK) — not IRAK2 — transmits the lipopolysaccharide signal within the cell.4

James A. Thomas, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75235-9148

4 References

1. 1

   Modlin RL, Brightbill HD, Godowski PJ. The toll of innate immunity on microbial pathogens. N Engl J Med 1999;340:1834-1835
   Full Text | Web of Science | Medline

2. 2

   Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282:2085-2088
   CrossRef | Web of Science | Medline

3. 3

   Heine H, Kirschning CJ, Lien E, Monks BG, Rothe M, Golenbock DT. Cutting edge: cells that carry a null allele for toll-like receptor 2 are capable of responding to endotoxin. J Immunol 1999;162:6971-6975
   Web of Science | Medline

4. 4

   Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A. The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J Exp Med 1998;187:2097-2101
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In our paper, we summarized the initial studies that demonstrated important roles for TLR2 and TLR4 in controlling the innate response to microbial pathogens. On the basis of the work of Poltorak et al.,1 we concluded that “functional TLR4 is essential to defend against gram-negative pathogens.” More recent studies2 have supported the view that TLR4 is essential for responses to gram-negative bacteria and lipopolysaccharide, whereas TLR2 is essential for the response to lipoproteins. Expression of the TLR2 gene in heterologous cells confers responsiveness to lipopolysaccharide, and an anti-TLR2 monoclonal antibody can block lipopolysaccharide-induced production of interleukin-12 by human adherent monocytes. Moreover, disruption of TLR2 in mice does not impair responses to lipopolysaccharide.3 Figure 1 of our article showed a speculative model of TLR2-mediated activation of NF-κB. This model was based on biochemical data showing that dominant negative versions of MyD88, tumor necrosis factor–receptor–associated factor 6, and IRAK (but not IRAK2, as depicted in the figure) can block activation of NF-κB by TLR2.4

Robert L. Modlin, M.D.
Hans D. Brightbill, B.S.
UCLA School of Medicine, Los Angeles, CA 90095

Paul J. Godowski, Ph.D.
Genentech, San Francisco, CA 94080

4 References

1. 1

   Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282:2085-2088
   CrossRef | Web of Science | Medline

2. 2

   Ulevitch RJ. Toll gates for pathogen selection. Nature 1999;401:755-756
   CrossRef | Web of Science | Medline

3. 3

   Takeuchi O, Hoshino K, Kawai T, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999;11:443-451
   CrossRef | Web of Science | Medline

4. 4

   Yang R-B, Mark MR, Gurney AL, Godowski PJ. Signaling events induced by lipopolysaccharide-activated toll-like receptor 2. J Immunol 1999;163:639-643
   Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Yoshihide Kimura, Koichi Sato, Hiroshi Tokuda, Naka Nakamura, Yasuaki Dohi, Etsuro Orito, Masashi Mizokami. (2007) Effects of Combination Therapy with Direct Hemoperfusion Using Polymyxin B-Immobilized Fiber and Oral Vancomycin on Fulminant Pseudomembranous Colitis with Septic Shock. Digestive Diseases and Sciences 52:3, 675-678
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2. 2

   Hideo Wada. (2004) Disseminated intravascular coagulation. Clinica Chimica Acta 344:1-2, 13-21
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