Critical role of nuclear factor‐κB and stress‐activated protein kinases in steroid unresponsiveness

Bantel, Heike; Schmitz, M. Lienhard; Raible, Armin; Gregor, Michael; Schulze‐Osthoff, Klaus

doi:10.1096/fj.02-0223fje

Cited by 101 publications

(67 citation statements)

References 55 publications

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“…Consistent with these mechanistic proposals is the observation that corticosteroid-resistant asthmatics exhibit increased levels of JNK signalling pathway proteins and heightened JNK activity [60]. A similar observation has been made in patients with Crohn's disease [61]. Whether or not JNK inhibitors represent an alternative therapy for this difficult-to-treat group of patients remains to be seen.…”

Section: C-jun N-terminal Kinase Inhibitors and Glucocorticoidsmentioning

confidence: 64%

c-Jun N-terminal kinase-dependent mechanisms in respiratory disease

Bennett¹

2006

European Respiratory Journal

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Section: C-jun N-terminal Kinase Inhibitors and Glucocorticoidsmentioning

confidence: 64%

c-Jun N-terminal kinase-dependent mechanisms in respiratory disease

Bennett¹

2006

European Respiratory Journal

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“…These findings validated the results from in-vitro cell culture studies [14] . Interestingly, increased JNK activation has also been shown in steroidresistant patients [15] . The significance of this finding is currently unclear.…”

Section: Role Of Jnk In Ibdmentioning

confidence: 95%

Role of the JNK signal transduction pathway in inflammatory bowel disease

Roy

Rashid²,

Bragg³

et al. 2008

WJG

125

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The c-Jun NH2-terminal Kinase (JNK) pathway represents one sub-group of the mitogen-activated protein (MAP) kinases which plays an important role in various inflammatory diseases states, including inflammatory bowel disease (IBD). Significant progress towards understanding the function of the JNK signaling pathway has been achieved during the past few years. Blockade of the JNK pathway with JNK inhibitors in animal models of IBD lead to resolution of intestinal inflammation. Current data suggest specific JNK inhibitors hold promise as novel therapies in IBD.

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“…However, over 60% of steroid-resistant patients had a different staining pattern with active NF-B predominantly localized in epithelial cells. The same investigators subsequently showed that while the activation of AP-1 and the upstream kinases p38 and c-Jun N-terminal kinase (JNK) in steroid-sensitive patients with CD was mainly found in lamina propria macrophages, steroid-resistant patients revealed activation of all these mediators mostly in epithelial cells (Bantel et al 2002). The functional interference of these proinflammatory mediators with the glucocorticoid response was supported by reporter gene assays with expression of NF-B, JNK and p38 all inhibiting the activity of GR .…”

Section: Inflammation Nf-b and Glucocorticoid Resistancementioning

confidence: 99%

Glucocorticoid resistance in inflammatory bowel disease

Rj¹,

Kelleher²

2003

Journal of Endocrinology

218

122

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Glucocorticoids are potent inhibitors of T cell activation and proinflammatory cytokines and are highly effective treatment for active inflammatory bowel disease (IBD). However, failure to respond, acutely or chronically, to glucocorticoid therapy is a common indication for surgery in IBD, with as many as 50% of patients with Crohn's disease (CD) and approximately 20% of patients with ulcerative colitis (UC) requiring surgery in their lifetime as a result of poor response to glucocorticoids. Studies report that approximately one-third of patients with CD are steroid dependent and one-fifth are steroid resistant while approximately one-quarter of patients with UC are steroid dependent and one-sixth are steroid resistant. While the molecular basis of glucocorticoid resistance has been widely assessed in other inflammatory conditions, the pathophysiology of the glucocorticoid resistance in IBD is poorly understood. Research in IBD suggests that the phenomenon of glucocorticoid resistance is compartmentalised to T-lymphocytes and possibly other target inflammatory cells. This review focuses on three key molecular mechanisms of glucocorticoid resistance in IBD: (i) decreased cytoplasmic glucocorticoid concentration secondary to increased P-glycoprotein-mediated efflux of glucocorticoid from target cells due to overexpression of the multidrug resistance gene (MDR1); (ii) impaired glucocorticoid signaling because of dysfunction at the level of the glucocorticoid receptor; and (iii) constitutive epithelial activation of proinflammatory mediators, including nuclear factor kappa B, resulting in inhibition of glucocorticoid receptor transcriptional activity. In addition, the impact of disease heterogeneity on glucocorticoid responsiveness and recent advances in IBD pharmacogenetics are discussed.

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Critical role of nuclear factor‐κB and stress‐activated protein kinases in steroid unresponsiveness

Cited by 101 publications

References 55 publications

c-Jun N-terminal kinase-dependent mechanisms in respiratory disease

c-Jun N-terminal kinase-dependent mechanisms in respiratory disease

Role of the JNK signal transduction pathway in inflammatory bowel disease

Glucocorticoid resistance in inflammatory bowel disease

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