Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

Malemud, Charles J.

doi:10.4172/2155-9899.s3-006

Cited by 11 publications

(20 citation statements)

References 176 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As previously reported [99,100], XIAP was localized to both the cytoplasm and nucleus, but XIAP and another anti-apoptosis protein, survivin, were highly expressed in the cytoplasm of cells in active RA synovial tissue [101]. Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) [38] mediated inhibition of XIAP activity may favor induction of apoptosis over cell survival under these conditions [31,38]. In addition, XIAP and other IAP proteins can directly inhibit caspase-3 and caspase-7 activity [102] as well as modulate the Bax/cytochrome C apoptosis pathway via XIAP-mediated inhibition of caspase-9 [103].…”

Section: Sapk/mapk Activation: Effects On Inhibitor Of Apoptosis Protmentioning

confidence: 77%

“…Thus, dysfunctional intracellular signaling induced by pro-inflammatory cytokines was shown to be responsible for aberrant immune-cell survival [31-33], articular chondrocyte apoptosis [33,34] and/or “apoptosis-resistance” of cells in RA synovial tissue [35-38]. Abnormalities in the aforementioned JAK/ STAT, SAPK/MAPK and PI-3K/AKT/mTOR pathways [26,27,39-41] as well as aberrant activities in spleen tyrosine kinase (Syk) [42-46], the sphingosine kinases, SphK1 and SphK2 [47-52], transforming growth factor β-activated kinase-1 (TAK1) [53], bone marrow kinase (BMX) [54] and nuclear factor-κB-inducing kinase (NIK) [55] have all been found in patients with active RA.…”

Section: Intracellular Signaling Regulates Immune-cell Synoviocyte Smentioning

confidence: 99%

“…In turn, c-IAPs were shown to regulate TNF-α-mediated signaling [89] and downstream MAPK activation, including ERK-1, -2, the latter being important regulators of the biological activity of hemopoietic progenitor cells in RA synovium [91] and the oncoprotein transcription factor, c-Myc, by articular chondrocytes in response to mechanical stimulation which also involved integrin-linked kinase and B-Raf [92]. Over-expression of c-Myc is considered essential for maintaining the continuously proliferating phenotype of transformed cells [93], which is in all likelihood, a property relevant to the uncontrolled proliferation and the “apoptosis-resistant” phenotype of RA synovium [38]. …”

Section: Sapk/mapk Activation: Effects On Inhibitor Of Apoptosis Protmentioning

confidence: 99%

“…Fas-like inhibitory protein (FLIP) (Figure 1) can block further downstream induction of apoptosis. Thus, cells which expressed high levels of FLIP had low “mature” caspase-8 activity [30,38]. …”

Section: Sapk/mapk Activation: Effects On Inhibitor Of Apoptosis Protmentioning

confidence: 99%

See 3 more Smart Citations

Intracellular Signaling Pathways in Rheumatoid Arthritis

Malemud¹

2013

J Clin Cell Immunol

111

View full text Add to dashboard Cite

Dysfunctional intracellular signaling involving deregulated activation of the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and “cross-talk” between JAK/STAT and the stress-activated protein kinase/mitogen-activated protein kinase (SAPK/MAPK) and Phosphatidylinositide-3-Kinase/AKT/mammalian Target of Rapamycin (PI-3K/AKT/mTOR) pathways play a critical role in rheumatoid arthritis. This is exemplified by immune-mediated chronic inflammation, up-regulated matrix metalloproteinase gene expression, induction of articular chondrocyte apoptosis and “apoptosis-resistance” in rheumatoid synovial tissue. An important consideration in the development of novel therapeutics for rheumatoid arthritis will be the extent to which inhibiting these signal transduction pathways will sufficiently suppress immune cell-mediated inflammation to produce a lasting clinical remission and halt the progression of rheumatoid arthritis pathology. In that regard, the majority of the evidence accumulated over the past decade indicated that merely suppressing pro-inflammatory cytokine-mediated JAK/ STAT, SAPK/MAPK or PI-3K/AKT/mTOR activation in RA patients may be necessary but not sufficient to result in clinical improvement. Thus, targeting aberrant enzyme activities of spleen tyrosine kinase, sphingosine kinases-1, -2, transforming growth factor β-activated kinase-1, bone marrow kinase, and nuclear factor-κB-inducing kinase for intervention may also have to be considered.

show abstract

Section: Sapk/mapk Activation: Effects On Inhibitor Of Apoptosis Protmentioning

confidence: 77%

Section: Intracellular Signaling Regulates Immune-cell Synoviocyte Smentioning

confidence: 99%

Section: Sapk/mapk Activation: Effects On Inhibitor Of Apoptosis Protmentioning

confidence: 99%

Section: Sapk/mapk Activation: Effects On Inhibitor Of Apoptosis Protmentioning

confidence: 99%

See 2 more Smart Citations

Intracellular Signaling Pathways in Rheumatoid Arthritis

Malemud¹

2013

J Clin Cell Immunol

111

View full text Add to dashboard Cite

show abstract

“…In RA the synovial joint structural damage is also accompanied by "apoptosis-resistance" in the hyperplastic synovial tissue [9][10][11][12] as well as by an increase in the number of apoptotic articular chondrocytes, which significantly affects attempts at cartilage repair [13][14][15]. From a molecular and pathophysiologic perspective the destruction of the RA synovial joints is further facilitated by aberrant signal transduction [16], by up-regulation of pro-inflammatory cytokine gene expression [17], and by increased chemokine and adhesion protein synthesis [18,19].…”

Section: Introductionmentioning

confidence: 99%