Molecular Pathogenesis of Endometriosis; Toll-Like Receptor-4 A896G (D299G) Polymorphism: A Novel Explanation

Latha, Madhavi; Vaidya, Sirisha; Movva, Sireesha; Chava, Srinivas; Govindan, Sujatha; Govatati, Suresh; Banoori, Manjula; Hasan, Qurratulain; Kodati, Vijay Lakshmi

doi:10.1089/gtmb.2010.0178

Cited by 21 publications

(14 citation statements)

References 20 publications

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“…20 Recent data reveal an association between Toll-like receptor-4 A896G (D299G) polymorphism and endometriosis. 21 This polymorphism is functional, resulting in peritoneal inflammation that is favorable for the endometrial cells in the initiation of endometriosis.…”

Section: Genetics Of Endometriosismentioning

confidence: 99%

Immunological Aspects of Endometriosis: An Update

Olovsson

2011

American J Rep Immunol

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Citation Olovsson M. Immunological Aspects of Endometriosis: An Update. Am J Reprod Immunol 2011; 66 (Suppl. 1): 101–104ProblemEndometriosis is a very complex disease that profoundly affects the quality of life of many women.Method of studyA review of the relationships between the female immune system and the occurrence and development of endometriosis.ResultsFunction and dysfunction of the female immune system plays important roles in the initiation and progression of the disease and its relation to infertility and cancer.ConclusionsOwing to obvious associations between endometriosis and the immune system, future treatment strategies might be based on immunological concepts and methods.

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Section: Genetics Of Endometriosismentioning

confidence: 99%

Immunological Aspects of Endometriosis: An Update

Olovsson

2011

American J Rep Immunol

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“…The D299G polymorphism has also been linked to Boutonneuse fever (27), RSV infections in infants and young children (28, 29), HIV-associated tuberculosis (30, 31), Crohn’s disease (32), ulcerative colitis (33), endometriosis (34), and tonsillitis (35). Human subjects carrying the T399I polymorphism either exhibit a milder LPS-hyporesponsive phenotype or do not manifest it at all (36).…”

Section: Introductionmentioning

confidence: 99%

The Asp299Gly Polymorphism Alters TLR4 Signaling by Interfering with Recruitment of MyD88 and TRIF

Figueroa

Xiong

Song

et al. 2012

The Journal of Immunology

121

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Asp299Gly (D299G) and, to a lesser extent, Thr399Ile (T399I) TLR4 polymorphisms have been associated with Gram negative sepsis and other infectious diseases, but the mechanisms by which they affect TLR4 signaling are unclear. In this study, we determined the impact of the D299G and T399I polymorphisms on TLR4 expression, interactions with myeloid differentiation factor 2 (MD2), LPS binding, and LPS-mediated activation of the MyD88- and TIR domain-containing adapter inducing IFN-β (TRIF) signaling pathways. Complementation of human embryonic kidney 293/CD14/MD2 transfectants with wild-type (WT) or mutant yellow fluorescent protein (YFP)-tagged TLR4 variants revealed comparable total TLR4 expression, TLR4-MD-2 interactions, and LPS binding. FACS analyses with anti-TLR4 Ab showed only minimal changes in the cell surface levels of the D299G TLR4. Cells transfected with D299G TLR4 exhibited impaired LPS-induced phosphorylation of p38 and TANK binding kinase-1, activation of NF-κB and IFN regulatory factor 3, and induction of IL-8 and IFN-β mRNA, while T399I TLR4 did not cause statistically significant inhibition. In contrast to WT TLR4, expression of the D299G mutants in TLR4−/− mouse macrophages failed to elicit LPS-mediated induction of TNF-α and IFN-β mRNA. Co-immunoprecipitation revealed diminished LPS-driven interaction of MyD88 and TRIF with the D299G TLR4 species, in contrast to robust adapter recruitment exhibited by WT TLR4. Thus, the D299G polymorphism compromises recruitment of MyD88 and TRIF to TLR4 without affecting TLR4 expression, TLR4-MD-2 interaction, or LPS binding, suggesting that it interferes with TLR4 dimerization and assembly of intracellular docking platforms for adapter recruitment.

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“…Moreover, a TLR-4 polymorphism associated with hypo-responsiveness of the receptor may result in peritoneal inflammation. Thus, endometrial cells tend to adhere to the peritoneum, a condition that may induce the initiation of endometriosis 11. We found that PRRs other than TLR-3 and TLR-4 are involved in immune reactions in patients with endometriosis of the peritoneal cavity.…”

Section: Discussionmentioning

confidence: 79%

Increased Expression of Pattern Recognition Receptors and Nitric Oxide Synthase in Patients with Endometriosis

Yeo

Won²,

Lee³

et al. 2013

Int. J. Med. Sci.

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Objective: Endometriosis is characterized by repeated inflammatory changes and serious adhesions, inducing innate and adaptive immune responses within the abdominal cavity. To assess these immune responses, we evaluated the levels of expression of Toll-like receptors (TLR)-1, -2, -4, -5, and -9; nucleotide-binding oligomerization domains (NOD)-1 and -2; interleukins-1β, -6, -8, -10, and -12; interferon-γ; tumor necrosis factor-α; inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS); and immunoglobulins (Igs) in patients with endometriosis.Methods: The levels of TLRs, NODs, cytokines, and NOS mRNAs in peritoneal effusions were assessed by real time reverse transcription-polymerase chain reaction; and IgG, IgA and IgM concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in 40 patients with and 40 without endometriosis. Findings from the two groups were compared.Results: We observed expression of all pattern recognition receptors (PRRs), cytokines, and NOS mRNAs and Igs in the effusion fluid of patients with and without endometriosis. The levels of TLR-2 and -9; NOD-1 and -2; iNOS and eNOS mRNAs and CA 125 were significantly higher in the endometriosis than in the non-endometriosis group (p<0.05 each). Moreover, PRR, cytokine, and NOS expression showed significant correlations (p<0.05).Conclusions: PRRs, cytokines, and NOS, which act cooperatively in the innate immune response, are closely associated with endometriosis. Increased expression of TLR-2, TLR -9, NOD-1, NOD-2, and NOS mRNA in peritoneal fluid may be associated with endometriosis.

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Molecular Pathogenesis of Endometriosis; Toll-Like Receptor-4 A896G (D299G) Polymorphism: A Novel Explanation

Cited by 21 publications

References 20 publications

Immunological Aspects of Endometriosis: An Update

Immunological Aspects of Endometriosis: An Update

The Asp299Gly Polymorphism Alters TLR4 Signaling by Interfering with Recruitment of MyD88 and TRIF

Increased Expression of Pattern Recognition Receptors and Nitric Oxide Synthase in Patients with Endometriosis

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