Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives

Chikanza, Ian C.; Kozacı, Didem

doi:10.1093/rheumatology/keh333

Cited by 59 publications

(42 citation statements)

References 104 publications

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“…Although the issue of glucocorticoid resistance in RA treatment is less well studied than in cancer treatment (24,31), it has been recognized to be of clinical importance in RA treatment as well (32,33). In the treatment of patients with systemic lupus erythematosus, drug combinations of HCQ and prednisone have also been used without apparent signs of drug resistance (34).…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistically, it is also possible that one of the nonlysosomotropic modes of action of CQ (i.e., inhibition of the MAP kinase signaling pathway [36,37]) has down-regulated signaling and interactions with GR␣ (25,33). Stimulation of PKA activity by forskolin could then, temporarily, restore GR- glucocorticoid-induced apoptosis and antiproliferative effects.…”

Section: Discussionmentioning

confidence: 99%

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Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Oerlemans

Heijden

Vink

et al. 2006

Arthritis & Rheumatism

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Objective. To explore the onset and molecular mechanism of resistance to the antimalarial diseasemodifying antirheumatic drug (DMARD) chloroquine (CQ) in human CEM T cells.Methods. Human CEM cells were used as an in vitro model system to study the development of CQ resistance by growing cells in stepwise increasing concentrations of CQ.Results. Over a period of 6 months, CEM cell lines developed 4-5-fold resistance to CQ. CQ resistance was associated with the specific overexpression of multidrug resistance-associated protein 1 (MRP-1), an ATP-driven drug efflux pump. This was illustrated by 1) overexpression of MRP-1 by Western blotting and 2) the complete reversal of CQ resistance by the MRP-1 transport inhibitors MK571 and probenecid. Importantly, CQ-resistant CEM cells retained full sensitivity to other DMARDs, including methotrexate, leflunomide, cyclosporin A, and sulfasalazine, but exhibited a high level of cross-resistance (>1,000-fold) to the glucocorticoid dexamethasone. The mechanistic basis for the latter was associated with aberrant signaling via the cAMP-protein kinase A pathway, since the cAMP-inducing agent forskolin reversed dexamethasone resistance. Finally, CQ-resistant CEM cells displayed a markedly reduced capacity to release proinflammatory cytokines (tumor necrosis factor ␣) and chemokines (interleukin-8).Conclusion. Induction of overexpression of the multidrug resistance efflux transporter MRP-1 can emerge after long-term exposure to CQ and results in CQ resistance and collateral resistance to dexamethasone. These findings warrant further detailed investigations into the possible role of MRP-1 and other members of the superfamily of drug efflux pumps in diminishing the efficacy of DMARDs in rheumatoid arthritis treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Oerlemans

Heijden

Vink

et al. 2006

Arthritis & Rheumatism

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“…This phenomenon could basically contribute to the pathomechanism of RA [17]. Van Osten et al have shown that in rheumatoid arthritis (RA), GC sensitivity is determined by acquired and genetic factors.…”

Section: Response To Glucocorticoids In Autoimmune Disordersmentioning

confidence: 99%

The Influence of Tissue-Specific Glucocorticoid System on the Inflammatory Microenviroment: A Mini-Review

Szappanos¹

2015

Immunome Res

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Glucocorticoids have been belonged to the most widely and commonly used immune modulatory drugs in autoimmune and inflammatory conditions. The anti-inflammatory and immune suppressant mechanisms have been described. However, the glucocorticoids have paracrine and autocrine manner, acting at local tissue level and that is called as "tissue-specific" glucocorticoids. Those have a significant role in the development of inflammation. The glucocorticoid receptors, the sensitivity for glucocorticoids and the hypothalamic-pituitary-adrenal (HPA) axis are associated strongly in the development, treatment and outcome of the inflammatory diseases. Dysregulation of the immune system and the endogenous glucocorticoid system may contribute to the pathogenesis of chronic autoimmune and inflammatory diseases.

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“…These drugs are closely related to the hormone cortisol and attenuate inflammation by downregulating pro-inflammatory cytokines such as TNFa, IL-1b and IL-6 [21]. Steroids are beneficial in that they relieve symptoms and slow joint damage but on the downside they are also responsible for the development of many unwanted side effects such as osteoporosis, diabetes and cataracts [22].…”

Section: Current Treatment Options For Rheumatoid Arthritismentioning

confidence: 99%

Proteinase-Activated Receptors and Arthritis

Russell

McDougall

2011

Proteases and Their Receptors in Inflammation

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The novel family of proteinase-activated receptors (PARs) is activated through proteolytic cleavage by serine proteinases. This family of G proteincoupled receptors and their activating enzymes are found widely throughout the body. It has been known for some time that during arthritic conditions, high levels of serine proteinases are released from joint tissue and contribute to joint degradation. Expression of PARs is also enhanced in arthritic joints and act to mediate the intracellular signalling of the serine proteinases, leading to various inflammatory and painful effects. This chapter summarises what is known so far on all four of the currently known PARs with respect to their links with arthritis and discusses how these receptors may represent novel targets for the development of new arthritic treatments.

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Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives

Cited by 59 publications

References 104 publications

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

The Influence of Tissue-Specific Glucocorticoid System on the Inflammatory Microenviroment: A Mini-Review

Proteinase-Activated Receptors and Arthritis

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