cytochrome-c-t and Psoriasis

Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis (PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation.

Topics: Animals; Apoptosis; Arthritis, Psoriatic; Autoimmunity; Cytochromes c; Humans; Oxidative Stress; Psoriasis; Tryptases

Psoriasis is a common autoimmune skin disease. The aim of this study was to investigate whether the apoptotic process is disturbed in psoriatic keratinocytes. In vitro culture of keratinocytes derived from both involved and uninvolved psoriatic skin, revealed higher viability and resistance to apoptosis following exposure to ultraviolet B, compared with cells from healthy controls. The position of apoptotic dysregulation was found to be upstream of cytochrome c release in the mitochondrial apoptotic pathway. Microarray transcriptome analysis revealed that 87 genes were differentially expressed in both involved and uninvolved psoriatic keratinocytes compared with controls. Among these, a general upregulation of anti-apoptotic genes and downregulation of pro-apoptotic genes were identified. This distinct apoptosis-resistant phenotype, unrelated to the inflammatory component of the disease, implies that intrinsic abnormalities in keratinocytes may contribute to the pathogenesis of psoriasis.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Case-Control Studies; Cells, Cultured; Cytochromes c; Epidermis; Gene Expression Profiling; Gene Expression Regulation; Humans; Keratinocytes; Mitochondria; Psoriasis; Radiation Tolerance; Ultraviolet Rays

Oxidative-free radicals and apoptosis have linked to chronic skin diseases. Higher levels of oxidative radicals and the release of mitochondrial cytochrome c may have a role in the pathogenesis of psoriasis. We investigated the possible role of cellular oxidative stress and release of cytochrome c of mitochondria in the pathogenesis of psoriasis. Disease severity was assessed by psoriasis area severity index score (PASI) of 55 psoriasis patients, they grouped as mild (11), moderate (20) and severe (24), also 20 healthy individuals used as controls. All groups were subjected for serum malondialdehyde (MDA), nitric oxide (NO·), superoxide dismutase (SOD), catalase (CAT), total antioxidant status (TAS) and serum cytochrome c concentrations. We found that, (1) Severity wise increase in MDA and NO·, and decrease in SOD, CAT and TAS levels in all patients with different degrees of psoriasis; (2) PASI showed positive correlation with the increase in MDA and NO·, and negatively with decreased SOD, CAT and TAS levels; (3) significant increase in cytochrome c level was observed among psoriasis patients which showed negative correlation to MDA and NO· levels in mild and positively with moderate and severe groups. The release of mitochondrial cytochrome c indicates the induction of apoptosis mediated via oxidative stress which ultimately plays role in the pathogenesis of psoriasis.

Topics: Adolescent; Adult; Aged; Cytochromes c; Female; Humans; Male; Malondialdehyde; Middle Aged; Nitric Oxide; Oxidative Stress; Psoriasis; Superoxide Dismutase

Anthralin is a potent topical drug, inducing clearance of psoriatic plaques. Anthralin disrupts mitochondrial function and structure, but its mechanism of action remains undefined. This study aimed to determine whether anthralin induced keratinocyte apoptosis as well as to investigate molecular mechanisms and the role of mitochondria. We studied human keratinocytes and human 143B rho(0) cells, which lack mitochondrial DNA and a functional respiratory chain. We show that anthralin disrupts mitochondrial membrane potential (DeltaPsim) and causes endogenous cytochrome c release, resulting in the activation of caspase-3 and characteristic morphological changes of apoptosis. Disruption of DeltaPsim and cytochrome c release were independent of mitochondrial permeability transition or caspase activation. Human 143B rho(0) cells were resistant to anthralin-induced cell death, disruption of DeltaPsim, and cytochrome c release compared with the isogenic 143B rho+ cell line. Using the intrinsic fluorescence of anthralin, rapid accumulation within mitochondria was observed independent of DeltaPsim. Using assays that measure individual respiratory chain complexes, we show that anthralin specifically interacts with ubiquinone pool. These data indicate that anthralin induces apoptosis through a novel mitochondrial pathway dependent on oxidative respiration and involving electron transfer with the ubiquinone pool. These studies identify keratinocyte apoptosis as a potentially important mechanism involved in the clearance of psoriasis.

Topics: Anthralin; Anti-Inflammatory Agents; Apoptosis; Caspase 3; Caspases; Cells, Cultured; Cytochromes c; DNA Fragmentation; DNA, Mitochondrial; Electron Transport; Enzyme Activation; Fluorescent Antibody Technique; Humans; Keratinocytes; Membrane Potentials; Mitochondria; Oxygen Consumption; Psoriasis; Ubiquinone