Similar Structures but Different Roles – An Updated Perspective on TLR Structures

Manavalan, Balachandran; Basith, Shaherin; Choi, Sangdun

doi:10.3389/fphys.2011.00041

Cited by 76 publications

(70 citation statements)

References 87 publications

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“…Residue F126 is located in the core of the (TLR4/MD-2)/(TLR4/ MD-2) oligomerization interface and initiates structural changes in MD-2 upon LPS binding. These conformational changes facilitated hydrogen bonds and electrostatic interactions between the F126 loop residues of MD-2 and a second copy of TLR4, stabilizing the dimeric (TLR4/MD-2)/(TLR4/MD-2) heterotetramer complex (21). Mutation of F126 and the surrounding residues in MD-2 blocked LPS-induced oligomerization (8).…”

Section: Resultsmentioning

confidence: 99%

Morphine activates neuroinflammation in a manner parallel to endotoxin

Wang

Loram²,

Ramos³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

394

449

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Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein-protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.protein-protein interaction | pain management therapy | drug discovery

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Section: Resultsmentioning

confidence: 99%

Morphine activates neuroinflammation in a manner parallel to endotoxin

Wang

Loram²,

Ramos³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

394

449

View full text Add to dashboard Cite

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“…27 TLR signaling represents one of the key mechanisms involved in these processes. 28 Although ATF3, an ATF4 homologue, has been reported to participate in the TLR4 signaling pathway 8,29 and recent reports have indicated that ATF4 is capable of regulating cytokine secretion, 9 it remains unclear whether ATF4 plays a role in TLR signaling. In this study, we defined a novel mechanism in which ATF4 is recruited by TLR4 signaling via the MyD88-dependent pathway, translocates to the nucleus and stimulates TLR-triggered cytokine production to further promote an inflammatory reaction.…”

Section: Discussionmentioning

confidence: 99%

ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes

et al. 2012

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Toll-like receptors (TLRs) are sentinels of the host defense system, which recognize a large number of microbial pathogens. The host defense system may be inefficient or inflammatory diseases may develop if microbial recognition by TLRs and subsequent TLR-triggered cytokine production are deregulated. Activating transcription factor 4 (ATF4), a member of the ATF/CREB transcription factor family, is an important factor that participates in several pathophysiological processes. In this report, we found that ATF4 is also involved in the TLR-mediated innate immune response, which participates in TLR4 signal transduction and mediates the secretion of a variety of cytokines. We observed that ATF4 is activated and translocates to the nucleus following lipopolysaccharide (LPS) stimulation via the TLR4-MyD88-dependent pathway. Additionally, a cytokine array assay showed that some key inflammatory cytokines, such as IL-6, IL-8 and RANTES, are positively regulated by ATF4. We also demonstrate that c-Jun directly binds to ATF4, thereby promoting the secretion of inflammatory cytokines. Taken together, these results indicate that ATF4 acts as a positive regulator in TLR4-triggered cytokine production.

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“…As our understanding of innate immunity has developed, our interest in applying this knowledge to clinical problems has also increased. Most of these translational efforts have been centered on TLRs, which are members of one of the largest and most well-studied family of PRRs (Basith et al, 2011). Moreover, the awarding of the prestigious Nobel Prize in Physiology or Medicine (2011) to Bruce Beutler and Jules Hoffmann for their discoveries concerning the activation of innate immunity underscores the timeliness and significance of this research.…”

Section: Introductionmentioning

confidence: 97%

Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense

et al. 2012

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Toll-like receptors (TLRs) belong to a class of pattern-recognition receptors that play an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs). Besides driving inflammatory responses, TLRs also regulate cell proliferation and survival by expanding useful immune cells and integrating inflammatory responses and tissue repair processes. TLR signaling, which is centrally involved in the initiation of both innate and adaptive immune responses, has been thought to be restricted to immune cells. However, recent studies have shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in tumor biology. Increasing bodies of evidence have suggested that TLRs act as a double-edged sword in cancer cells because uncontrolled TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response. Alternatively, TLRs can induce an antitumor immune response in order to inhibit tumor progression. In this review, we summarize the dual roles of TLRs in tumor cells and, more importantly, delve into the therapeutic potential of TLRs in the context of tumorigenesis.

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Similar Structures but Different Roles – An Updated Perspective on TLR Structures

Cited by 76 publications

References 87 publications

Morphine activates neuroinflammation in a manner parallel to endotoxin

Morphine activates neuroinflammation in a manner parallel to endotoxin

ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes

Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense

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