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Sheila Macneil - One of the best experts on this subject based on the ideXlab platform.
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transglutaminase inhibitors induce hyperproliferation and parakeratosis in tissue engineered skin
British Journal of Dermatology, 2007Co-Authors: Caroline A. Harrison, Christopher Layton, Anthony J Bullock, Timothy S Johnson, Sheila MacneilAbstract:BACKGROUND: The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross-linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross-linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue-engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis. OBJECTIVES: Accordingly, this study was designed to study the effect of pan-transglutaminase inhibition on morphology of tissue-engineered skin and expression of keratinocyte differentiation and proliferation-associated antigens. METHODS: We used a tissue-engineered model of human skin, based on de-epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air-liquid interface. The pan-transglutaminase inhibitors putrescine, NTU283 (1-dimethyl,2-[(oxopropyl)thio]imidazolium) and NTU285 (N-benzyloxycarbonyl-l-glutaminyl-6-dimethylsulfonium-5-oxo-l-norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and Cytokeratins 6, 10 and 16 were performed. RESULTS: Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and Cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of Cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression. CONCLUSIONS: Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and Cytokeratins 6 and 16. Expression of the differentiation-associated Cytokeratin, Cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.
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Transglutaminase inhibitors induce hyperproliferation and parakeratosis in tissue-engineered skin.
The British journal of dermatology, 2007Co-Authors: Caroline A. Harrison, Christopher Layton, Anthony J Bullock, Timothy S Johnson, Z. Hau, Sheila MacneilAbstract:Summary Background The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross-linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross-linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue-engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis. Objectives Accordingly, this study was designed to study the effect of pan-transglutaminase inhibition on morphology of tissue-engineered skin and expression of keratinocyte differentiation and proliferation-associated antigens. Methods We used a tissue-engineered model of human skin, based on de-epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air–liquid interface. The pan-transglutaminase inhibitors putrescine, NTU283 (1-dimethyl,2-[(oxopropyl)thio]imidazolium) and NTU285 (N-benzyloxycarbonyl-l-glutaminyl-6-dimethylsulfonium-5-oxo-l-norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and Cytokeratins 6, 10 and 16 were performed. Results Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and Cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of Cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression. Conclusions Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and Cytokeratins 6 and 16. Expression of the differentiation-associated Cytokeratin, Cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.
Caroline A. Harrison - One of the best experts on this subject based on the ideXlab platform.
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transglutaminase inhibitors induce hyperproliferation and parakeratosis in tissue engineered skin
British Journal of Dermatology, 2007Co-Authors: Caroline A. Harrison, Christopher Layton, Anthony J Bullock, Timothy S Johnson, Sheila MacneilAbstract:BACKGROUND: The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross-linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross-linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue-engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis. OBJECTIVES: Accordingly, this study was designed to study the effect of pan-transglutaminase inhibition on morphology of tissue-engineered skin and expression of keratinocyte differentiation and proliferation-associated antigens. METHODS: We used a tissue-engineered model of human skin, based on de-epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air-liquid interface. The pan-transglutaminase inhibitors putrescine, NTU283 (1-dimethyl,2-[(oxopropyl)thio]imidazolium) and NTU285 (N-benzyloxycarbonyl-l-glutaminyl-6-dimethylsulfonium-5-oxo-l-norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and Cytokeratins 6, 10 and 16 were performed. RESULTS: Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and Cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of Cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression. CONCLUSIONS: Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and Cytokeratins 6 and 16. Expression of the differentiation-associated Cytokeratin, Cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.
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Transglutaminase inhibitors induce hyperproliferation and parakeratosis in tissue-engineered skin.
The British journal of dermatology, 2007Co-Authors: Caroline A. Harrison, Christopher Layton, Anthony J Bullock, Timothy S Johnson, Z. Hau, Sheila MacneilAbstract:Summary Background The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross-linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross-linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue-engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis. Objectives Accordingly, this study was designed to study the effect of pan-transglutaminase inhibition on morphology of tissue-engineered skin and expression of keratinocyte differentiation and proliferation-associated antigens. Methods We used a tissue-engineered model of human skin, based on de-epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air–liquid interface. The pan-transglutaminase inhibitors putrescine, NTU283 (1-dimethyl,2-[(oxopropyl)thio]imidazolium) and NTU285 (N-benzyloxycarbonyl-l-glutaminyl-6-dimethylsulfonium-5-oxo-l-norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and Cytokeratins 6, 10 and 16 were performed. Results Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and Cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of Cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression. Conclusions Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and Cytokeratins 6 and 16. Expression of the differentiation-associated Cytokeratin, Cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.
Samuel W. French - One of the best experts on this subject based on the ideXlab platform.
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mallory body Cytokeratin aggresomes formation is prevented in vitro by p38 inhibitor
Experimental and Molecular Pathology, 2006Co-Authors: Li Nan, Barbara A. French, Fawzia Bardaggorce, Jennifer Dedes, Samuel W. FrenchAbstract:Microarray analysis of livers from mice fed diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) to induce Mallory body (MB) Cytokeratin aggresome formation showed that gene expression for cellular adhesion molecules, Cytokeratins, kinases and aggresome forming proteins were upregulated, when MBs were formed in vivo. This response was enhanced when the DDC was refed (mice fed DDC for 10 weeks followed by DDC withdrawal for 1 month, then refed DDC for 7 days). Immunofluorescent antibody staining of the MBs that formed showed that MAPK p38 was colocalized with ubiquitin and p62 in the MBs. To investigate further the mechanisms of MB formation, primary cultures derived from DDC primed mice and their controls were incubated for 6 days. Liver cells cultured for 3 h and 6 days were used for microarray analysis. At 3 h, there were no MBs formed, but MBs were numerous after 6 days of culture. At 3 h, the expression of a large number of genes was different when the control, and the DDC primed hepatocytes were compared, which indicates that the primed hepatocytes were phenotypically changed. The gene expression of many kinases including p38 was upregulated after 6 days where the gene expression of Cytokeratins, adhesion molecules and aggresome forming proteins were upregulated when MBs formed. An inhibitor of p38 phosphorylation (SB202190) completely prevented MB formation. Western blot showed that phosphorylated p38 MAPK and total p38 were absent in vitro after the p38 inhibitor treatment. Immunostaining of 6-day DDC-primed hepatocyte cultures stained with antibodies to p62 and phospho-p38 MAPK showed that phosphorylated p38 MAPK was concentrated within the MBs. Antibodies to specific serine phosphorylated sites 73 and 431, located in Cytokeratin 8, localized to Mallory bodies in vivo, indicating that Cytokeratin 8 was hyperphosphorylated. The data supported the concept that MBs form as the result of hyperphosphorylation of Cytokeratin 8 by p38.
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the proteasome inhibitor ps 341 causes Cytokeratin aggresome formation
Experimental and Molecular Pathology, 2004Co-Authors: Fawzia Bardaggorce, Li Nan, Barbara A. French, Nora E. Riley, Yan He Lue, Rosalyn O Montgomery, Samuel W. FrenchAbstract:Abstract Mallory body (MB) experimental induction takes 10 weeks of drug ingestion. Therefore, it is difficult to study the dynamics and mechanisms involved in vivo. Consequently, an in vitro study was done using primary tissue culture of hepatocytes from drug-primed mice livers in which MBs had already formed. The hypothesis to be tested was that MBs are Cytokeratin aggresomes, which form when hepatocytes have a defective ubiquitin–proteasome pathway by which turnover of Cytokeratin proteins is prevented. To test this hypothesis, primary tissue cultures of the hepatocytes from normal and MB-forming livers were incubated with the proteasome inhibitor PS-341 and then the Cytokeratin filaments and the filament connecting proteins, that is, β-actin, and ZO1, were visualized by immunofluorescence microscopy. PS-341 caused detachment of the Cytokeratins from the cell surface plasma membrane. The Cytokeratin filaments retracted toward the nucleus and Cytokeratin aggresomes formed. In human livers, MBs showed colocalization of Cytokeratin-8 (CK-8) with ubiquitin but not with β-actin or ZO1. Mouse hepatoma cell lines were studied using PS-341 to induce Cytokeratin aggresome formation. In these cell lines, the Cytokeratin filaments first retracted toward the nucleus then formed Cytokeratin–ubiquitin aggresomes polarized at one side of the nucleus. At the same time, the cells became dissociated from each other, however. The results simulated MB formation. MBs differ from Cytokeratin aggresomes both morphologically and in ultrastructure.
Anthony J Bullock - One of the best experts on this subject based on the ideXlab platform.
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transglutaminase inhibitors induce hyperproliferation and parakeratosis in tissue engineered skin
British Journal of Dermatology, 2007Co-Authors: Caroline A. Harrison, Christopher Layton, Anthony J Bullock, Timothy S Johnson, Sheila MacneilAbstract:BACKGROUND: The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross-linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross-linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue-engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis. OBJECTIVES: Accordingly, this study was designed to study the effect of pan-transglutaminase inhibition on morphology of tissue-engineered skin and expression of keratinocyte differentiation and proliferation-associated antigens. METHODS: We used a tissue-engineered model of human skin, based on de-epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air-liquid interface. The pan-transglutaminase inhibitors putrescine, NTU283 (1-dimethyl,2-[(oxopropyl)thio]imidazolium) and NTU285 (N-benzyloxycarbonyl-l-glutaminyl-6-dimethylsulfonium-5-oxo-l-norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and Cytokeratins 6, 10 and 16 were performed. RESULTS: Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and Cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of Cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression. CONCLUSIONS: Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and Cytokeratins 6 and 16. Expression of the differentiation-associated Cytokeratin, Cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.
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Transglutaminase inhibitors induce hyperproliferation and parakeratosis in tissue-engineered skin.
The British journal of dermatology, 2007Co-Authors: Caroline A. Harrison, Christopher Layton, Anthony J Bullock, Timothy S Johnson, Z. Hau, Sheila MacneilAbstract:Summary Background The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross-linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross-linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue-engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis. Objectives Accordingly, this study was designed to study the effect of pan-transglutaminase inhibition on morphology of tissue-engineered skin and expression of keratinocyte differentiation and proliferation-associated antigens. Methods We used a tissue-engineered model of human skin, based on de-epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air–liquid interface. The pan-transglutaminase inhibitors putrescine, NTU283 (1-dimethyl,2-[(oxopropyl)thio]imidazolium) and NTU285 (N-benzyloxycarbonyl-l-glutaminyl-6-dimethylsulfonium-5-oxo-l-norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and Cytokeratins 6, 10 and 16 were performed. Results Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and Cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of Cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression. Conclusions Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and Cytokeratins 6 and 16. Expression of the differentiation-associated Cytokeratin, Cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.
Timothy S Johnson - One of the best experts on this subject based on the ideXlab platform.
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transglutaminase inhibitors induce hyperproliferation and parakeratosis in tissue engineered skin
British Journal of Dermatology, 2007Co-Authors: Caroline A. Harrison, Christopher Layton, Anthony J Bullock, Timothy S Johnson, Sheila MacneilAbstract:BACKGROUND: The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross-linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross-linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue-engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis. OBJECTIVES: Accordingly, this study was designed to study the effect of pan-transglutaminase inhibition on morphology of tissue-engineered skin and expression of keratinocyte differentiation and proliferation-associated antigens. METHODS: We used a tissue-engineered model of human skin, based on de-epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air-liquid interface. The pan-transglutaminase inhibitors putrescine, NTU283 (1-dimethyl,2-[(oxopropyl)thio]imidazolium) and NTU285 (N-benzyloxycarbonyl-l-glutaminyl-6-dimethylsulfonium-5-oxo-l-norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and Cytokeratins 6, 10 and 16 were performed. RESULTS: Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and Cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of Cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression. CONCLUSIONS: Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and Cytokeratins 6 and 16. Expression of the differentiation-associated Cytokeratin, Cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.
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Transglutaminase inhibitors induce hyperproliferation and parakeratosis in tissue-engineered skin.
The British journal of dermatology, 2007Co-Authors: Caroline A. Harrison, Christopher Layton, Anthony J Bullock, Timothy S Johnson, Z. Hau, Sheila MacneilAbstract:Summary Background The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross-linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross-linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue-engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis. Objectives Accordingly, this study was designed to study the effect of pan-transglutaminase inhibition on morphology of tissue-engineered skin and expression of keratinocyte differentiation and proliferation-associated antigens. Methods We used a tissue-engineered model of human skin, based on de-epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air–liquid interface. The pan-transglutaminase inhibitors putrescine, NTU283 (1-dimethyl,2-[(oxopropyl)thio]imidazolium) and NTU285 (N-benzyloxycarbonyl-l-glutaminyl-6-dimethylsulfonium-5-oxo-l-norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and Cytokeratins 6, 10 and 16 were performed. Results Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and Cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of Cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression. Conclusions Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and Cytokeratins 6 and 16. Expression of the differentiation-associated Cytokeratin, Cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.
