Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis

Padyukov, Leonid; Lampa, Jon; Heimbürger, Mikael; Ernestam, Sofia; Cederholm, Tommy; Lundkvist, Inger; Andersson, Per Ola; Hermansson, Y; Harju, Anders; Klareskog, Lars; Bratt, Johan

doi:10.1136/ard.62.6.526

Cited by 181 publications

(134 citation statements)

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“…It is well established that dysregulation of the inflammatory cascade is a major contributing factor to the development of chronic inflammation. Even though critical roles of certain proinflammatory cytokines have been well established in the pathogenesis of chronic inflammatory disorders (1,2), the genetic regulation and cellular responses mediated by inflammatory cytokines appear to be heterogenous (3). This heterogeneity may be due to the induction of different diseaseassociated pathways in different patients, or it may reflect different stages of the disease, or both (4).…”

mentioning

confidence: 99%

Inflammatory Cytokines IL-32 and IL-17 Have Common Signaling Intermediates despite Differential Dependence on TNF-Receptor 1

Turner-Brannen

Choi

Arsenault³

et al. 2011

The Journal of Immunology

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Cytokines IL-32 and IL-17 are emerging as critical players in the pathophysiology of immune-mediated chronic inflammatory diseases. It has been speculated that the molecular mechanisms governing IL-32– and IL-17–mediated cellular responses are differentially dependent on the TNF pathway. In this study, kinome analysis demonstrated that following stimulation with cytokine IL-32, but not IL-17, there was increased phosphorylation of a peptide target corresponding to TNF-R1. Consistent with this observation, blocking TNF-R1 resulted in a suppression of IL-32–induced downstream responses, indicating that IL-32–mediated activity may be dependent on TNF-R1. In contrast, blocking TNF-R1 did not affect IL-17–induced downstream responses. Kinome analysis also implicated p300 (transcriptional coactivator) and death-associated protein kinase-1 (DAPK-1) as signaling intermediates for both IL-32 and IL-17. Phosphorylation of p300 and DAPK-1 upon stimulation with either IL-32 or IL-17 was confirmed by immunoblots. The presence of common targets was supported by results demonstrating similar downstream responses induced in the presence of IL-32 and IL-17, such as transcriptional responses and the direct activation of NF-κB. Furthermore, knockdown of p300 and DAPK-1 altered downstream responses induced by IL-32 and IL-17, and impacted certain cellular responses induced by TNF-α and IL-1β. We hypothesize that p300 and DAPK-1 represent nodes where the inflammatory networks of IL-32 and IL-17 overlap, and that these proteins would affect both TNF-R1–dependent and –independent pathways. Therefore, p300 and DAPK-1 are viable potential therapeutic targets for chronic inflammatory diseases.

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confidence: 99%

Inflammatory Cytokines IL-32 and IL-17 Have Common Signaling Intermediates despite Differential Dependence on TNF-Receptor 1

Turner-Brannen

Choi

Arsenault³

et al. 2011

The Journal of Immunology

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“…The difference in the response has been reported in biologic response modifiers. 5,6 Moreover, the use of these agents is limited by the development of unpredictable toxicities that are sometimes severe. Previously, it was described that the activities of some drug-metabolizing enzymes for DMARDs, such as Nacetyltransferase 2 (NAT2) for SSZ 7 and thiopurine methyltransferase (TPMT) for azathioprine (AZA), 8 are different among individuals.…”

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confidence: 99%

“…However, 20-40% of patients have been reported as nonresponders. 6 For biologic response modifiers targeting inflammatory cytokines, polymorphisms associated with the genes that regulate either the production or the function of the cytokines may influence the response to these agents. 6 Previous studies showed that A allele at À308GA polymorphism within the TNF-a gene (TNFA) promoter might be related to the high production of TNF-a.…”

mentioning

confidence: 99%

“…6 For biologic response modifiers targeting inflammatory cytokines, polymorphisms associated with the genes that regulate either the production or the function of the cytokines may influence the response to these agents. 6 Previous studies showed that A allele at À308GA polymorphism within the TNF-a gene (TNFA) promoter might be related to the high production of TNF-a. 32,33 Mugnier et al 34 reported that A/A or A/G genotypes at À308 position of TNFA were associated with a poor response to infliximab therapy.…”

mentioning

confidence: 99%

“…6 Although larger-scale studies including genotypes on various cytokines, cytokine receptors or antagonists will be needed, these studies suggested that the pharmacogenetic approach may be useful for predicting efficacy of anti-TNF-a treatment and for saving medical cost because these agents are extremely expensive.…”

mentioning

confidence: 99%

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