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Apoptotic pathways in pemphigus.

Bektas M, Jolly P, Rubenstein DS - Dermatol Res Pract (2010)

Bottom Line: Pemphigus is a group of human autoimmune blistering diseases of the skin in which autoantibodies to desmosome cadherins induce loss of cell-cell adhesion (acantholysis).In addition to steric hindrance and activation of intracellular signaling, apoptosis has been suggested to contribute to the mechanism by which pathogenic IgG induces acantholysis.Current data suggest that apoptosis is not required for blister induction, but that activation of proapoptotic proteins, including caspase cysteine proteinases, may sensitize cells to the acantholytic effects of pemphigus IgG.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.

ABSTRACT
Pemphigus is a group of human autoimmune blistering diseases of the skin in which autoantibodies to desmosome cadherins induce loss of cell-cell adhesion (acantholysis). In addition to steric hindrance and activation of intracellular signaling, apoptosis has been suggested to contribute to the mechanism by which pathogenic IgG induces acantholysis. We review the current literature examining the role of apoptosis in pemphigus. Current data suggest that apoptosis is not required for blister induction, but that activation of proapoptotic proteins, including caspase cysteine proteinases, may sensitize cells to the acantholytic effects of pemphigus IgG.

No MeSH data available.


Related in: MedlinePlus

Pemphigus, p38MAPK, acantholysis and apoptosis. Two sequential peaks of p38MAPK activation are observed when keratinocytes are exposed to either PV or PF IgG. (a) Pemphigus IgG binds to dsg and biases the equilibrium of desmosome assembly/disassembly towards disassembly which is linked by an, as yet, undefined mechanism towards activation of p38MAPK. Subsequent p38 dependent alterations in the cell state include RhoA inactivation, dsg endocytosis, HSP27 phosphorylation, keratin intermediate filament retraction, actin, and loss of cell-cell adhesion (acantholysis). (b) A second late peak of p38 activity is observed that is likely a stress response signal induced by loss of cell-cell adhesion and leads to activation of proapoptotic pathways including caspase-3 activation.
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fig1: Pemphigus, p38MAPK, acantholysis and apoptosis. Two sequential peaks of p38MAPK activation are observed when keratinocytes are exposed to either PV or PF IgG. (a) Pemphigus IgG binds to dsg and biases the equilibrium of desmosome assembly/disassembly towards disassembly which is linked by an, as yet, undefined mechanism towards activation of p38MAPK. Subsequent p38 dependent alterations in the cell state include RhoA inactivation, dsg endocytosis, HSP27 phosphorylation, keratin intermediate filament retraction, actin, and loss of cell-cell adhesion (acantholysis). (b) A second late peak of p38 activity is observed that is likely a stress response signal induced by loss of cell-cell adhesion and leads to activation of proapoptotic pathways including caspase-3 activation.

Mentions: To investigate the relationship of the first and second peak of p38MAPK activity to acantholysis, and apoptosis, inhibitor experiments were performed in both primary human keratinocyte culture and passive transfer mouse models. By either pretreating cultures or mice with p38MAPK inhibitors prior to pemphigus IgG or at a time after the first, but prior to the second peak of p38MAPK activity, either both peaks or the second peak of p38MAPK activity could be selectively inhibited. Utilizing this approach, inhibition of the first, but not second, peak of p38MAPK activity inhibited blister formation in vivo and cytokeratin retraction in vitro [55]. We interpreted these results to indicate that the first, but not second peak, of p38MAPK activity observed after exposure to pemphigus IgG was part of the mechanism of acantholysis. Importantly, although it failed to inhibit cytokeratin retraction and acantholysis, selective inhibition of the later second peak of p38MAPK activity inhibited caspase-3 activation in vivo. Thus, the time course studies revealed that apoptosis occurs at or after the second peak of p38MAPK activation and that inhibition of this later peak of p38MAPK activity blocked activation of the proapoptotic proteinase caspase-3, but not acantholysis. Collectively, these observations suggest that the earlier peak of p38MAPK activation is part of the mechanism leading to acantholysis; whereas, the later peak of p38MAPK and apoptosis are subsequent to and likely not essential for acantholysis (Figure 1).


Apoptotic pathways in pemphigus.

Bektas M, Jolly P, Rubenstein DS - Dermatol Res Pract (2010)

Pemphigus, p38MAPK, acantholysis and apoptosis. Two sequential peaks of p38MAPK activation are observed when keratinocytes are exposed to either PV or PF IgG. (a) Pemphigus IgG binds to dsg and biases the equilibrium of desmosome assembly/disassembly towards disassembly which is linked by an, as yet, undefined mechanism towards activation of p38MAPK. Subsequent p38 dependent alterations in the cell state include RhoA inactivation, dsg endocytosis, HSP27 phosphorylation, keratin intermediate filament retraction, actin, and loss of cell-cell adhesion (acantholysis). (b) A second late peak of p38 activity is observed that is likely a stress response signal induced by loss of cell-cell adhesion and leads to activation of proapoptotic pathways including caspase-3 activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2902125&req=5

fig1: Pemphigus, p38MAPK, acantholysis and apoptosis. Two sequential peaks of p38MAPK activation are observed when keratinocytes are exposed to either PV or PF IgG. (a) Pemphigus IgG binds to dsg and biases the equilibrium of desmosome assembly/disassembly towards disassembly which is linked by an, as yet, undefined mechanism towards activation of p38MAPK. Subsequent p38 dependent alterations in the cell state include RhoA inactivation, dsg endocytosis, HSP27 phosphorylation, keratin intermediate filament retraction, actin, and loss of cell-cell adhesion (acantholysis). (b) A second late peak of p38 activity is observed that is likely a stress response signal induced by loss of cell-cell adhesion and leads to activation of proapoptotic pathways including caspase-3 activation.
Mentions: To investigate the relationship of the first and second peak of p38MAPK activity to acantholysis, and apoptosis, inhibitor experiments were performed in both primary human keratinocyte culture and passive transfer mouse models. By either pretreating cultures or mice with p38MAPK inhibitors prior to pemphigus IgG or at a time after the first, but prior to the second peak of p38MAPK activity, either both peaks or the second peak of p38MAPK activity could be selectively inhibited. Utilizing this approach, inhibition of the first, but not second, peak of p38MAPK activity inhibited blister formation in vivo and cytokeratin retraction in vitro [55]. We interpreted these results to indicate that the first, but not second peak, of p38MAPK activity observed after exposure to pemphigus IgG was part of the mechanism of acantholysis. Importantly, although it failed to inhibit cytokeratin retraction and acantholysis, selective inhibition of the later second peak of p38MAPK activity inhibited caspase-3 activation in vivo. Thus, the time course studies revealed that apoptosis occurs at or after the second peak of p38MAPK activation and that inhibition of this later peak of p38MAPK activity blocked activation of the proapoptotic proteinase caspase-3, but not acantholysis. Collectively, these observations suggest that the earlier peak of p38MAPK activation is part of the mechanism leading to acantholysis; whereas, the later peak of p38MAPK and apoptosis are subsequent to and likely not essential for acantholysis (Figure 1).

Bottom Line: Pemphigus is a group of human autoimmune blistering diseases of the skin in which autoantibodies to desmosome cadherins induce loss of cell-cell adhesion (acantholysis).In addition to steric hindrance and activation of intracellular signaling, apoptosis has been suggested to contribute to the mechanism by which pathogenic IgG induces acantholysis.Current data suggest that apoptosis is not required for blister induction, but that activation of proapoptotic proteins, including caspase cysteine proteinases, may sensitize cells to the acantholytic effects of pemphigus IgG.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.

ABSTRACT
Pemphigus is a group of human autoimmune blistering diseases of the skin in which autoantibodies to desmosome cadherins induce loss of cell-cell adhesion (acantholysis). In addition to steric hindrance and activation of intracellular signaling, apoptosis has been suggested to contribute to the mechanism by which pathogenic IgG induces acantholysis. We review the current literature examining the role of apoptosis in pemphigus. Current data suggest that apoptosis is not required for blister induction, but that activation of proapoptotic proteins, including caspase cysteine proteinases, may sensitize cells to the acantholytic effects of pemphigus IgG.

No MeSH data available.


Related in: MedlinePlus