Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation.
Immunosuppressants are used ubiquitously post-liver transplantation to prevent allograft rejection. However their effects on hepatocytes are unknown. Experimental data from non-liver cells indicate that immunosuppressants may promote cell death thereby driving an inflammatory response that promotes...
| Κύριοι συγγραφείς: | , , , , , , |
|---|---|
| Μορφή: | Άρθρο |
| Γλώσσα: | English |
| Έκδοση: |
Public Library of Science (PLoS)
2015-01-01
|
| Σειρά: | PLoS ONE |
| Διαθέσιμο Online: | http://europepmc.org/articles/PMC4577231?pdf=render |
| _version_ | 1828838260071202816 |
|---|---|
| author | Eu Jin Lim Ruth Chin Ueli Nachbur John Silke Zhiyuan Jia Peter W Angus Joseph Torresi |
| author_facet | Eu Jin Lim Ruth Chin Ueli Nachbur John Silke Zhiyuan Jia Peter W Angus Joseph Torresi |
| author_sort | Eu Jin Lim |
| collection | DOAJ |
| description | Immunosuppressants are used ubiquitously post-liver transplantation to prevent allograft rejection. However their effects on hepatocytes are unknown. Experimental data from non-liver cells indicate that immunosuppressants may promote cell death thereby driving an inflammatory response that promotes fibrosis and raises concerns that a similar effect may occur within the liver. We evaluated apoptosis within the liver tissue of post-liver transplant patients and correlated these findings with in vitro experiments investigating the effects of immunosuppressants on apoptosis in primary hepatocytes.Hepatocyte apoptosis was assessed using immunohistochemistry for M30 CytoDEATH and cleaved PARP in human liver tissue. Primary mouse hepatocytes were treated with various combinations of cyclosporine, tacrolimus, sirolimus, or MMF. Cell viability and apoptosis were evaluated using crystal violet assays and Western immunoblots probed for cleaved PARP and cleaved caspase 3.Post-liver transplant patients had a 4.9-fold and 1.7-fold increase in M30 CytoDEATH and cleaved PARP compared to normal subjects. Cyclosporine and tacrolimus at therapeutic concentrations did not affect hepatocyte apoptosis, however when they were combined with MMF, cell death was significantly enhanced. Cell viability was reduced by 46% and 41%, cleaved PARP was increased 2.6-fold and 2.2-fold, and cleaved caspase 3 increased 2.2-fold and 1.8-fold following treatment with Cyclosporine/MMF and Tacrolimus/MMF respectively. By contrast, the sirolimus/MMF combination did not significantly reduce hepatocyte viability or promote apoptosis.Commonly used immunosuppressive drug regimens employed after liver transplantation enhance hepatocyte cell death and may thus contribute to the increased liver fibrosis that occurs in a proportion of liver transplant recipients. |
| first_indexed | 2024-12-12T18:58:55Z |
| format | Article |
| id | doaj.art-f61b51a8725f43a9833ddd56cd7e706a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T18:58:55Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f61b51a8725f43a9833ddd56cd7e706a2022-12-22T00:15:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01109e013852210.1371/journal.pone.0138522Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation.Eu Jin LimRuth ChinUeli NachburJohn SilkeZhiyuan JiaPeter W AngusJoseph TorresiImmunosuppressants are used ubiquitously post-liver transplantation to prevent allograft rejection. However their effects on hepatocytes are unknown. Experimental data from non-liver cells indicate that immunosuppressants may promote cell death thereby driving an inflammatory response that promotes fibrosis and raises concerns that a similar effect may occur within the liver. We evaluated apoptosis within the liver tissue of post-liver transplant patients and correlated these findings with in vitro experiments investigating the effects of immunosuppressants on apoptosis in primary hepatocytes.Hepatocyte apoptosis was assessed using immunohistochemistry for M30 CytoDEATH and cleaved PARP in human liver tissue. Primary mouse hepatocytes were treated with various combinations of cyclosporine, tacrolimus, sirolimus, or MMF. Cell viability and apoptosis were evaluated using crystal violet assays and Western immunoblots probed for cleaved PARP and cleaved caspase 3.Post-liver transplant patients had a 4.9-fold and 1.7-fold increase in M30 CytoDEATH and cleaved PARP compared to normal subjects. Cyclosporine and tacrolimus at therapeutic concentrations did not affect hepatocyte apoptosis, however when they were combined with MMF, cell death was significantly enhanced. Cell viability was reduced by 46% and 41%, cleaved PARP was increased 2.6-fold and 2.2-fold, and cleaved caspase 3 increased 2.2-fold and 1.8-fold following treatment with Cyclosporine/MMF and Tacrolimus/MMF respectively. By contrast, the sirolimus/MMF combination did not significantly reduce hepatocyte viability or promote apoptosis.Commonly used immunosuppressive drug regimens employed after liver transplantation enhance hepatocyte cell death and may thus contribute to the increased liver fibrosis that occurs in a proportion of liver transplant recipients.http://europepmc.org/articles/PMC4577231?pdf=render |
| spellingShingle | Eu Jin Lim Ruth Chin Ueli Nachbur John Silke Zhiyuan Jia Peter W Angus Joseph Torresi Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation. PLoS ONE |
| title | Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation. |
| title_full | Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation. |
| title_fullStr | Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation. |
| title_full_unstemmed | Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation. |
| title_short | Effect of Immunosuppressive Agents on Hepatocyte Apoptosis Post-Liver Transplantation. |
| title_sort | effect of immunosuppressive agents on hepatocyte apoptosis post liver transplantation |
| url | http://europepmc.org/articles/PMC4577231?pdf=render |
| work_keys_str_mv | AT eujinlim effectofimmunosuppressiveagentsonhepatocyteapoptosispostlivertransplantation AT ruthchin effectofimmunosuppressiveagentsonhepatocyteapoptosispostlivertransplantation AT uelinachbur effectofimmunosuppressiveagentsonhepatocyteapoptosispostlivertransplantation AT johnsilke effectofimmunosuppressiveagentsonhepatocyteapoptosispostlivertransplantation AT zhiyuanjia effectofimmunosuppressiveagentsonhepatocyteapoptosispostlivertransplantation AT peterwangus effectofimmunosuppressiveagentsonhepatocyteapoptosispostlivertransplantation AT josephtorresi effectofimmunosuppressiveagentsonhepatocyteapoptosispostlivertransplantation |