Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (IL-6) is a cytokine with redundant and pleiotropic activities, and its synthesis is tightly regulated by transcriptional and posttranscriptional mechanisms. When infections and tissue injuries occur, IL-6 synthesis is promptly induced and provides an emergent signal that contributes to host defense through the stimulation of acute-phase responses, immune reactions, and hematopoiesis. After the environmental stress is removed from the host, the production of IL-6 is terminated. However, dysregulated continual synthesis of IL-6 is involved in the development of chronic inflammatory autoimmune diseases. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Worldwide clinical trials have demonstrated the outstanding efficacy of tocilizumab in rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman's disease; thus, a new era has come for the treatment of these diseases, which were previously considered intractable. Moreover, favorable results from off-label use of tocilizumab strongly suggest that it will be widely applicable for various refractory inflammatory autoimmune diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated in order to investigate the pathogenesis of specific diseases and to facilitate the development of more specific therapeutic strategies.
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PMID:A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy. 2459 1

Castleman's disease (CD) is a benign lymphoproliferative disorder characterized by dysfunctional lymphatic node hyperplasia. Lymphatic node hyperplasia is associated with elevated levels of inhibitor of differentiation 1 (ID1) in many human tumors. To assess the possible role of ID1 expression as a prognostic marker in multicentric CD (MCD), intra-lymph node ID1 expression was analyzed and related to clinical characteristics and outcomes in 48 patients. Furthermore, the correlation between ID1 and possible signaling molecules such as interleukin-6 (IL6), phosphorylated extracellular response kinase (p-ERK), and vascular endothelial growth factor C (VEGFC) was explored on six fresh MCD surgical specimens. Immunohistochemistry revealed that the patients with extensive ID1 expression had significantly poorer prognosis, compared to those with localized ID1. In addition, ID1 was positively associated with levels of IL6, p-ERK, and VEGFC. We conclude that ID1 may ultimately be a prognostic marker in MCD and that the IL6/ERK/VEGFC pathway is involved in the progress of this disease.
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PMID:Inhibitor of differentiation 1 is a candidate prognostic marker in multicentric Castleman's disease. 2459 83

Multicentric Castleman's disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of interleukin-6. Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment. Human herpes virus-8 (HHV-8) drives the hypercytokinemia in all HIV-positive patients and some HIV-negative patients. There is also a group of HIV-negative and HHV-8-negative patients with unknown etiology and pathophysiology, which we propose referring to as idiopathic MCD (iMCD). Here, we synthesize what is known about iMCD pathogenesis, present a new subclassification system, and propose a model of iMCD pathogenesis. MCD should be subdivided into HHV-8-associated MCD and HHV-8-negative MCD or iMCD. The lymphocyte proliferation, histopathology, and systemic features in iMCD are secondary to hypercytokinemia, which can occur with several other diseases. We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus. Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases.
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PMID:HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. 2462 27

Multicentric Castleman Disease (MCD) is a lymphoproliferative disorder presenting with heterogeneous pathological and clinical features. It comprises disease entities with a complex aetiology and overlapping pathogenesis. MCD can be found in association with HIV infection, plasma-cell dyscrasias, Kaposi sarcoma (KS), B-cell lymphomas including primary effusion lymphoma (PEL) and its solid variant, and Hodgkin lymphoma. In KSHV-associated MCD cases, a common association is KS and a specific variant of lymphoma referred to as "plasmablastic lymphoma," also called "large B-cell lymphoma arising in KSHV-associated MCD" lacking EBV infection. MCD is often referred to as human interleukin-6 (hIL-6) syndrome, since an overproduction of IL-6 occurs in MCD-associated diseases as well as in MCD itself. hIL-6 and a viral IL-6 (vIL-6) homolog encoded by KSHV can independently or together lead to flares of KSHV-associated MCD. Recently, a new clinical entity was proposed to describe a severe systemic infection/reactivation of KSHV: KSHV inflammatory syndrome (KICS). KICS may contribute in inducing the inflammatory symptoms seen in some patients with severe KS or PEL. The precise relationship of KICS to KSHV-associated MCD is unclear and it is possible that KICS may be prodromal symptoms to frank KSHV-associated MCD. Options for treatment of KSHV-associated MCD and related diseases include monoclonal antibodies, chemotherapy, immune modulators, virus-activated cytotoxic therapy and antiviral therapies. A comprehensive understanding of the intricacies of the HIV-KSHV coinfection will probably lead to additional advances in therapy and managements for these disorders.
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PMID:KSHV-associated multicentric Castleman disease: A tangle of different entities requiring multitarget treatment strategies. 2477 91

Interleukin-6 (IL-6) is a classic pro-inflammatory cytokine critical in mounting an effective immune response. It is secreted by a wide array of cell types; however, its effector cells are more restricted, owing to the fact that very few cells, except lymphocytes and hepatocytes, express the functional membrane IL-6 receptor thus reducing the number of IL-6-responsive cells. Trans-signalling, the shedding of the membrane-bound form of the IL-6 receptor into the local microenvironment, greatly increases the range of cells that can respond. IL-6 has been demonstrated to have a pivotal role in the pathogenesis of rheumatoid arthritis, Castleman's disease and Crohn's disease exemplified by the use of an anti-IL-6 biological therapy. However, IL-6 is also associated with the autoimmune disease systemic sclerosis (SSc) and has been shown to be directly fibrotic. Elevated levels of IL-6 are found in SSc patients and this correlates with skin thickness, suggesting a causal effect. This review focuses on the role of IL-6 in SSc, a chronic autoimmune disease with fibrosis. In particular, we will examine the evidence base of the role of IL-6 in fibrosis in this condition, especially the downstream effector pathways. We will then argue why molecular targeting of IL-6 is a promising therapeutic target in this fibrosing disease.
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PMID:Interleukin-6: a new therapeutic target in systemic sclerosis? 2550 52

Castleman's disease (CD) is a polyclonal lymphoproliferative disorder also known as giant nodular hyperplasia or angiofollicular lymph node hyperplasia. It is a rare disease often associated to human immunodeficiency virus (HIV) and human herpes virus 8 (HHV-8). Histopathological findings in Castleman's disease suggest an exaggerated response to antigenic stimuli seen in other diseases associated with immune activation, such as rheumatoid arthritis. An important aspect of its pathogenesis is the autonomous production of interleukin-6 (IL-6). In this disease, the clinical manifestations are associated to IL-6 serum levels, and surgical removal of the compromised lymph nodes or use of anti-IL-6 antibodies can slow down the symptoms. We describe a multicentric Castleman's disease in a young woman not associated to HHV-8 virus infection or immunosuppression. A short review of the literature follows the description of this clinical case.
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PMID:[Multicentric Castleman disease not associated with HHV-8 and HIV viruses]. 2562 30

Castleman's disease is a rare lymphoproliferative disorder the underlying mechanism of which remains unclear. However, interleukin-6 (IL-6) may play a role in the pathogenesis of the disease. Blockade of the IL-6 pathway has been explored in multiple preclinical and clinical studies with promising results for the treatment of different types of cancer and Castleman's disease. Siltuximab is a human/murine chimeric immunoglobulin G1kappa (IgG1kappa) monoclonal antibody against human IL-6. It binds to IL-6 neutralizing its biological activity. Recent phase II clinical studies in patients with multicentric Castleman's disease have shown the efficacy and safety of siltuximab in patients with this condition. Results from this study led to the recent approval of siltuximab for the treatment of Castleman's disease by the FDA and EMA.
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PMID:Siltuximab: a new option for the management of Castleman's disease. 2568 58

Interleukin-6 (IL-6) is a pro-inflammatory cytokine involved in the pathogenesis of various autoimmune and chronic inflammatory diseases. Binding of IL-6 to its receptor (IL-6R) initiates both classical- and trans-signaling pathways. A number of autoimmune diseases are characterized by overproduction of IL-6. Tocilizumab, a humanized monoclonal antibody against IL-6R, blocks IL-6-mediated signaling and has been approved for the treatment of rheumatoid arthritis and Castleman's disease. IL-6 levels are also upregulated in various tumors, and the levels of circulating IL-6 are associated with prognosis in cancer patients. The major issues covered in this commentary include (1) how IL-6-mediated biological effects may lead to the pathogenesis of autoimmune diseases and cancers, (2) the rationale of developing anti-IL-6 strategies for therapeutic purposes, (3) recent advances in anti-IL-6 therapeutics (clinical benefits and adverse events), (4) current knowledge about clinical trials evaluating newly emerging anti-IL-6 treatments, (5) strategies to improve anti-IL-6 therapeutics from both basic and clinical aspects. This commentary provides a useful overview of the role of IL-6 in both autoimmune diseases and cancers from the laboratory as well as clinical perspectives.
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PMID:Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers. 2608 5

Multicentric Castleman's disease is a systemic inflammatory disorder characterized by lymphadenopathy and excessive interleukin-6 production. A unique clinicopathologic variant of multicentric Castleman's disease, TAFRO (i.e., thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly) syndrome, was recently proposed in Japan. Despite the successful use of anti-interleukin-6 therapy in some patients with TAFRO syndrome, not all patients achieve remission. The pathophysiological etiology of and suitable therapeutic strategies for this variant have not been established. Here, we present our experience of a unique case of TAFRO syndrome in a 78-year-old woman whose symptoms responded differently to several therapies. Tocilizumab, an anti-interleukin-6 receptor antibody, successfully induced remission of fever and lymphadenopathy. However, severe thrombocytopenia persisted and she developed anasarca, ascites, and pleural effusion shortly thereafter. Rituximab, an anti-CD20 antibody, and glucocorticoid therapy provided no symptom relief. In contrast, cyclosporine A, an immunosuppressive agent that blocks T cell function by inhibiting interleukin-2, yielded immediate improvements in systemic fluid retention and a gradual increase in platelet count, with complete resolution of disease symptoms. Excessive serum interleukin-2, when used as an anti-cancer agent, has been reported to cause side effects such as fluid retention, thrombocytopenia, and renal failure. Our case was unique because the anti-interleukin-2 therapy successfully improved symptoms that were not relieved with anti-interleukin-6 therapy. The present report therefore provides insight into the possible role of interleukin-2, in addition to interleukin-6, in TAFRO syndrome. This report will certainly help to clarify the pathogenesis of and optimal treatment strategies for TAFRO syndrome.
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PMID:Successful Treatment of TAFRO Syndrome, a Variant of Multicentric Castleman's Disease, with Cyclosporine A: Possible Pathogenetic Contribution of Interleukin-2. 2625 May 36

Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman's Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology.
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PMID:Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo. 2655 95


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