Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

Arredondo, Juan; Chernyavsky, Alexander I.; Karaouni, Ali; Grando, Sergei A.

doi:10.1016/s0002-9440(10)61239-4

Cited by 111 publications

(151 citation statements)

References 83 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…Correlation between Biochemical and Phenotypic Changes in KCs Treated with PVIgG-We have previously reported that PVIgG-treated KCs shrink, detach from neighboring cells, and die through a mixed apoptotic/oncotic pathway, featuring TUNEL positivity (14,16). Keratinocyte shrinkage upon exposure to PVIgG (Fig.…”

Section: Time Course Study Of Kinase Activities In Kcs Exposed To Pvmentioning

confidence: 86%

“…Likewise, PVIgG induces Fas-ligand production in KCs (14), and Fas-ligand acts synergistically with PVIgG and TNF␣ in acantholysis induction (16). Fas signaling leads to apoptosis through the p38 MAPK step (24), which may provide a mechanism for engagement of this stress kinase in the acantholytic pathway.…”

Section: Discussionmentioning

confidence: 99%

“…were unequivocally positive. The IgG fractions were isolated by FPLC protein G affinity chromatography using the FPLC System purchased from Amersham Biosciences and following the manufacturer's protocol, as detailed by us elsewhere (14).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Chernyavsky

Arredondo

Kitajima

et al. 2007

Journal of Biological Chemistry

Self Cite

127

View full text Add to dashboard Cite

Although it is accepted that pemphigus antibody binding to keratinocytes (KCs) evokes an array of intracellular biochemical events resulting in cell detachment and death, the triggering events remain obscure. It has been postulated that the binding of pemphigus vulgaris IgG (PVIgG) to KCs induces "desmosomal" signaling. Because in contrast to integrins and classical cadherins, desmoglein (Dsg) molecules are not known to elicit intracellular signaling, and because PV patients also produce non-Dsg autoantibodies, we investigated the roles of both Dsg and non-desmoglein PV antigens. The time course studies of KCs treated with PVIgG demonstrated that the activity of Src peaked at 30 min, EGF receptor kinase (EGFRK) at 60 min, and p38 MAPK at 240 min. The Src inhibitor PP2 decreased EGFRK and p38 activities by ϳ45 and 30%, respectively, indicating that in addition to Src, PVIgG evokes other triggering events. The shrinkage of KCs (cell volume reduction) became significant at 120 min, keratin aggregation at 240 min, and an increase of TUNEL positivity at 360 min. Pretreatment of KCs with PP2 blocked PVIgG-dependent cell shrinkage and keratin aggregation by ϳ50% and TUNEL positivity by ϳ25%. The p38 MAPK inhibitor PD169316 inhibited these effects by ϳ15, 20, and 70%, respectively. Transfection of KCs with small interfering RNAs that silenced expression of Dsg1 and/or Dsg3 proteins, blocked ϳ50% of p38 MAPK activity but did not significantly alter the PVIgG-dependent rise in Src and EGFRK activities. These results indicate that activation of p38 MAPK is a late signaling step associated with collapse of the cytoskeleton and disassembly of desmosomes caused by upstream events involving Src and EGFRK. Therefore, the early acantholytic events are triggered by non-Dsg antibodies.

show abstract

Section: Time Course Study Of Kinase Activities In Kcs Exposed To Pvmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Chernyavsky

Arredondo

Kitajima

et al. 2007

Journal of Biological Chemistry

Self Cite

127

View full text Add to dashboard Cite

show abstract

“…We became interested in MtAbs because we sought to elucidate the mechanism of intrinsic apoptosis of KCs in PV originally demonstrated by us (17) and confirmed by others (18,19). The direct evidence that MtAbs are critical to disease pathology, rather than a bystander phenomena in PV, was provided by the studies demonstrating that PV IgGs enter KCs and specifically bind to a number of mitochondrial proteins, which is associated with the mitochondrial damage manifested by cytochrome c release (20).…”

Section: Pemphigus Vulgaris (Pv)mentioning

confidence: 96%

“…Morphometric Assay of Acantholysis in Vivo-PVIgGs were isolated by FPLC protein G affinity chromatography using the FPLC System purchased from Amersham Biosciences following the manufacturer's protocol, as detailed elsewhere (17). Minocycline, nicotinamide, and cyclosporine A were purchased from Sigma-Aldrich.…”

Section: Analysis Of Mitochondrial O 2 Respiration By Extracellular Fmentioning

confidence: 99%

Mechanisms of Mitochondrial Damage in Keratinocytes by Pemphigus Vulgaris Antibodies

Kalantari-Dehaghi

Chen²,

Deng³

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Previous studies suggested that mitochondrial antibodies contribute to pemphigus vulgaris (PV). Results: PV sera elicited mitochondrial damage, and mitochondria-protecting drugs exhibited protective effect in cell culture and mouse skin. Conclusion: PV antibodies altered O 2 respiration, disrupted electron transfer chain, and increased reactive oxygen species. Significance: Results provide the mechanism of therapeutic action and justify the use of mitochondria-protecting drugs in PV.

show abstract

The most widespread desmosomal cadherin, desmoglein 2, is a novel target of caspase 3‐mediated apoptotic machinery

Cirillo¹,

Lanza²,

Rosa³

et al. 2007

J of Cellular Biochemistry

View full text Add to dashboard Cite

Apoptotic cells are known to regulate the ordered dismantling of intercellular contacts through caspase activity. Despite the important role of desmoglein (Dsg) 2 in epithelial cell-cell adhesion, the fate of this widespread desmosomal cadherin during apoptosis is yet poorly understood. Here, by means of pharmacological approaches, we investigated whether Dsg2 was targeted by caspases in HaCaT and HT-29 cell lines undergoing staurosporine (STS)-induced apoptosis. Results showed that STS induced a caspase-dependent form of cell-death in both keratinocytes (HaCaT) and enterocytes (HT-29), that associated with progressive depletion of Dsg2 from cell lysates. The proteolytic processing of full-length Dsg2 resulted in the appearance of a 70-kDa fragment which was released into the cytosol. Consistently, immunofluorescence studies revealed that Dsg2 staining was abolished from cell surface whereas the cytoplasmic region of Dsg2 did localize intracellularly. Plakoglobin (Pg) also underwent cleavage and detached from Dsg2. Apoptotic changes paralleled with progressive loss of intercellular adhesion strength. All these biochemical, morphological, and functional changes were regulated by caspase 3. Indeed, in the presence of the caspase 3-inhibitor z-DEVD-fmk, full-length Dsg2 protein levels were preserved, whereas the amount of the 70-kDa fragment was maintained on control levels. Furthermore, cells pretreated with z-DEVD-fmk retained the membrane labeling of Dsg2. Taken together, our data demonstrate that the apoptotic processing of Dsg2 is mediated by caspase 3 in epithelial cells.

show abstract

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

Abstract: Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by cell-cell

Cited by 111 publications

References 83 publications

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Mechanisms of Mitochondrial Damage in Keratinocytes by Pemphigus Vulgaris Antibodies

The most widespread desmosomal cadherin, desmoglein 2, is a novel target of caspase 3‐mediated apoptotic machinery

Contact Info

Product

Resources

About