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Blood, 1 August 2007, Vol. 110, No. 3, pp. 794. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Takeuchi, O. Articles by Akira, S. Search for Related Content PubMed Articles by Takeuchi, O. Articles by Akira, S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Wang et al, page 962 TLR4 signaling: negative regulation by degradation Osamu Takeuchi, and Shizuo Akira OSAKA UNIVERSITY In this issue of Blood, Wang and colleagues describe that small GTPase Rab7b negatively regulates TLR4-mediated responses by promoting the translocation of TLR4 into lysosomes for its degradation. Toll-like receptors (TLRs) play a critical role in the recognition of microbial components in innate immune cells.1 Among 13 identified mammalian TLRs, TLR4 recognizes lipopolysaccharide (LPS) from Gram-negative bacteria. Activation of signaling cascades triggered by TLR4 stimulation leads to the up-regulation of proinflammatory cytokine and chemokine genes. Although TLR4 signaling is critical for eradicating Gram-negative bacterial infection, excess production of cytokines can cause endotoxic shock and death. Extensive studies have revealed that various host proteins act as negative regulators of TLR4 signaling and prevent aberrant activation of TLR4 signaling.2 These proteins include SIGIRR, ST2, the splice variant of MyD88 (MyD88s), IL-1R-associated kinase-M (IRAK-M), a protein associated with TLR4 (PRAT4A), A20, Triad3A, and so on. The complex mechanism of negative regulation of TLRs emphasizes that it is important for prevention of uncontrolled immune activation in the host. In this issue of Blood, Wang and colleagues report a novel mechanism for negative regulation of TLR4 signaling. This mechanism involves Rab7b small GTPase, which localized to lysosome-associated subcellular compartments. Rab7 has been shown to be involved in membrane trafficking and lysosomal degradation of several receptors, such as antigotensin II receptor EGFR and TrkA. The authors show that siRNA-mediated knockdown of the Rab7b gene in macrophages resulted in up-regulation of LPS-induced proinflammatory cytokine production. Reciprocally, overexpression of Rab7b suppressed TLR4-mediated production of cytokines as well as activation of intracellular signaling molecules. Upon stimulation, TLR4 is internalized and recruited to the late endosomes/lysosomes where Rab7b is located. In Rab7b-silenced cells, the expression of TLR4 was higher than in control cells, and translocation of TLR4 from early endosomes to late endosomes/lysosomes was delayed. This study clearly demonstrates that the down-regulation of TLR4 protein expression by Rab7b plays a critical role in the control of LPS responses. However, the mechanisms by which Rab7b controls TLR4 trafficking in a stimulant-dependent manner remain to be clarified. Further, it is possible that lysosome-mediated degradation is a common mechanism for the regulation of responses against various TLR ligands. Future studies regarding spatiotemporal regulation of TLR signaling molecules in the cell will shed light on the importance of membrane trafficking in the control of innate immune responses. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. REFERENCES Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124:783–801.[CrossRef][Medline] [Order article via Infotrieve] Liew FY, Xu D, Brint EK, O'Neill LA. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 2005; 5:446–458.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4 Yuzhen Wang, Taoyong Chen, Chaofeng Han, Donghua He, Haibo Liu, Huazhang An, Zhen Cai, and Xuetao Cao Blood 2007 110: 962-971. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Takeuchi, O. Articles by Akira, S. Search for Related Content PubMed Articles by Takeuchi, O. Articles by Akira, S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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