Molecular mechanisms of regulation of Toll-like receptor signaling

Leifer, Cynthia A.; Medvedev, Andrei E.

doi:10.1189/jlb.2mr0316-117rr

Cited by 206 publications

(171 citation statements)

References 212 publications

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“…The role of LTB 4 in TLR activation has been suggested [64–66]. TLR signaling induces pro-inflammatory cytokine responses [67, 68]. TLR2 is a cell surface receptor that senses peptidoglycan molecules commonly found on gram-positive bacteria and TLR9 is an endosomal receptor that detects DNA [67, 68].…”

Section: Effects Of Ltb4 On Host Defense Mechanismsmentioning

confidence: 99%

Too much of a good thing: How modulating LTB 4 actions restore host defense in homeostasis or disease

Brandt

Serezani

2017

Seminars in Immunology

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The ability to regulate inflammatory pathways and host defense mechanisms is critical for maintaining homeostasis and responding to infections and tissue injury. While unbalanced inflammation is detrimental to the host; inadequate inflammation might not provide effective signals required to eliminate pathogens. On the other hand, aberrant inflammation could result in organ damage and impair host defense. The lipid mediator leukotriene B4 (LTB4) is a potent neutrophil chemoattractant and recently, its role as a dominant molecule that amplifies many arms of phagocyte antimicrobial effector function has been unveiled. However, excessive LTB4 production contributes to disease severity in chronic inflammatory diseases such as diabetes and arthritis, which could potentially be involved in poor host defense in these groups of patients. In this review we discuss the cellular and molecular programs elicited during LTB4 production and actions on innate immunity host defense mechanisms as well as potential therapeutic strategies to improve host defense.

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Section: Effects Of Ltb4 On Host Defense Mechanismsmentioning

confidence: 99%

Too much of a good thing: How modulating LTB 4 actions restore host defense in homeostasis or disease

Brandt

Serezani

2017

Seminars in Immunology

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“…By recognizing pathogen-associated molecular patterns and damageassociated molecular patterns, TLRs alert surrounding cells to the presence of pathogens or cellular damage. 47 TLRs are activated through a conformational change upon binding a target ligand. This causes the activation of MyD88, which activates a signaling cascade leading to IRAK1 phosphorylation, IkB inactivation, and NF-kB nuclear translocation.…”

Section: Cytokines and Malignancy In Hlhmentioning

confidence: 99%

Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy

Vick¹,

Patel

Prouet

et al. 2017

Blood Advances

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Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of cytokine-driven immune activation. Cardinal features include fever, hemophagocytosis, hepatosplenomegaly, lymphocytic infiltration, and hypercytokinemia that result in multisystem organ dysfunction and failure. Familial HLH is genetically driven, whereas secondary HLH (SHL) is caused by drugs, autoimmune disease, infection, or cancer. SHL is associated with worse outcomes, with a median overall survival typically of less than 1 year. This reflects difficulty in both diagnostic accuracy and in establishing reliable treatments, especially in cases of malignancyinduced SHL, which have significantly worse outcomes. Malignancy-induced HLH is seen almost exclusively with hematologic malignancies, constituting 97% of cases in the literature over the past 2 years. In these situations, the native immune response driven by CD8 T cells produces an overabundance of T helper 1 cytokines, notably interferon-g, tumor necrosis factor-a, and interleukin-6, which establish a positive feedback loop of inflammation, enhancing replication of hematologic malignancies while leaving the host immune system in disarray. In this paper, we present 2 case studies of secondary HLH driven by HM, followed by a review of the literature discussing the cytokines driving HLH, diagnostic criteria, and current treatments used or undergoing investigation. Case 1A previously healthy 34-year-old male presented with progressive malaise, fevers, and abdominal discomfort. He was found to have massive splenomegaly along with pancytopenia and coagulopathy. Initial laboratory studies showed lactate dehydrogenase (LDH) 470 U/L, ferritin 4450 ng/dL, white blood cell count 1.3 3 10 9 /L, platelets 31 3 10 9 /L, hematocrit 22%, and fibrinogen level 130 mg/dL. A bone marrow (BM) biopsy was performed and showed lymphohistiocytic aggregation without hemophagocytosis. The patient underwent splenectomy; pathology showed splenic red pulp congestion and proliferation of sheets of normal histiocytes with marked erythrophagocytosis. No conclusive evidence of B-or T-cell lymphoma was found at that time, although features suggestive of but not diagnostic for T-cell rich diffuse large B-cell lymphoma (DLBCL) were seen in the spleen. The patient subsequently had a positron emission tomography/computed tomography scan and was found to have small hyperactive para-aortic lymph nodes that were not accessible for biopsy. The patient began therapy for HLH with dexamethasone and etoposide for 6 cycles and tolerated it well, with resolution of his laboratory abnormalities and symptoms.A year and a half after initial diagnosis, he presented to the hospital again with back pain and fevers. A computed tomography scan showed multiple retroperitoneal and periaortic lymph nodes along with liver lesions. He was started on dexamethasone and admitted to the hospital. Multiple lymph node biopsies were performed and were inconclusive, possibly from steroid pretreatment. Further evaluation with bilateral BM biopsies reported T-cell rich ...

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“…Новые исследования показали, что TLRs явля-ются ключевыми регуляторами как врожденного, так и адаптивного иммунного ответа, и пост-трансляционные модификации могут приводить к изменению их функциональной активности [24]. Изменение передачи сигналов TLRs модулиру-ет функцию дендритных клеток (ДК), связываю-щих врожденный и адаптивный иммунный ответ.…”

Section: рузультаты и обсуждениеunclassified

Early markers of phenotypic heterogeneity in the induced model of systemic lupus erythematosus

Колесникова¹,

Гойман²,

Демченко³

et al. 2017

Bûll. sib. med.

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Molecular mechanisms of regulation of Toll-like receptor signaling

Cited by 206 publications

References 212 publications

Too much of a good thing: How modulating LTB 4 actions restore host defense in homeostasis or disease

Too much of a good thing: How modulating LTB 4 actions restore host defense in homeostasis or disease

Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy

Early markers of phenotypic heterogeneity in the induced model of systemic lupus erythematosus

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