Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach
Thiopurines are extensively used immunosuppressants for the treatment of inflammatory bowel disease (IBD). The polymorphism of thiopurine S-methyltransferase (TPMT) influences thiopurine metabolism and therapy outcome. We used a TPMT knockdown (kd) model of human Jurkat T-lymphocytes cells to study...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2015-01-01
|
| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2015/434825 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832549787290828800 |
|---|---|
| author | Misbah Misdaq Sonia Ziegler Nicolas von Ahsen Michael Oellerich Abdul R. Asif |
| author_facet | Misbah Misdaq Sonia Ziegler Nicolas von Ahsen Michael Oellerich Abdul R. Asif |
| author_sort | Misbah Misdaq |
| collection | DOAJ |
| description | Thiopurines are extensively used immunosuppressants for the treatment of inflammatory bowel disease (IBD). The polymorphism of thiopurine S-methyltransferase (TPMT) influences thiopurine metabolism and therapy outcome. We used a TPMT knockdown (kd) model of human Jurkat T-lymphocytes cells to study the effects of treatment with 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) on proteome and phosphoproteome. We identified thirteen proteins with altered expression and nine proteins with altered phosphorylation signals. Three proteins (THIO, TXD17, and GSTM3) with putative functions in cellular oxidative stress responses were altered by 6-TG treatment and another protein PRDX3 was differentially phosphorylated in TPMT kd cells. Furthermore, reactive oxygen species (ROS) assay results were consistent with a significant induction of oxidative stress by both TPMT knockdown and thiopurine treatments. Immunoblot analyses showed treatment altered expression of key antioxidant enzymes (i.e., SOD2 and catalase) in both wt and kd groups, while SOD1 was downregulated by 6-TG treatment and TPMT knockdown. Collectively, increased oxidative stress might be a mechanism involved in thiopurine induced cytotoxicity and adverse effects (i.e., hepatotoxicity) and an antioxidant cotherapy might help to combat this. Results highlight the significance of oxidative stress in thiopurines’ actions and could have important implications for the treatment of IBD patients. |
| format | Article |
| id | doaj-art-482f0cfa100d4300badbc111f31ced39 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-482f0cfa100d4300badbc111f31ced392025-02-03T06:08:29ZengWileyMediators of Inflammation0962-93511466-18612015-01-01201510.1155/2015/434825434825Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic ApproachMisbah Misdaq0Sonia Ziegler1Nicolas von Ahsen2Michael Oellerich3Abdul R. Asif4Institute of Clinical Chemistry/UMG Laboratories, University Medical Centre Goettingen, 37075 Goettingen, GermanyInstitute of Clinical Chemistry/UMG Laboratories, University Medical Centre Goettingen, 37075 Goettingen, GermanyInstitute of Clinical Chemistry/UMG Laboratories, University Medical Centre Goettingen, 37075 Goettingen, GermanyInstitute of Clinical Chemistry/UMG Laboratories, University Medical Centre Goettingen, 37075 Goettingen, GermanyInstitute of Clinical Chemistry/UMG Laboratories, University Medical Centre Goettingen, 37075 Goettingen, GermanyThiopurines are extensively used immunosuppressants for the treatment of inflammatory bowel disease (IBD). The polymorphism of thiopurine S-methyltransferase (TPMT) influences thiopurine metabolism and therapy outcome. We used a TPMT knockdown (kd) model of human Jurkat T-lymphocytes cells to study the effects of treatment with 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) on proteome and phosphoproteome. We identified thirteen proteins with altered expression and nine proteins with altered phosphorylation signals. Three proteins (THIO, TXD17, and GSTM3) with putative functions in cellular oxidative stress responses were altered by 6-TG treatment and another protein PRDX3 was differentially phosphorylated in TPMT kd cells. Furthermore, reactive oxygen species (ROS) assay results were consistent with a significant induction of oxidative stress by both TPMT knockdown and thiopurine treatments. Immunoblot analyses showed treatment altered expression of key antioxidant enzymes (i.e., SOD2 and catalase) in both wt and kd groups, while SOD1 was downregulated by 6-TG treatment and TPMT knockdown. Collectively, increased oxidative stress might be a mechanism involved in thiopurine induced cytotoxicity and adverse effects (i.e., hepatotoxicity) and an antioxidant cotherapy might help to combat this. Results highlight the significance of oxidative stress in thiopurines’ actions and could have important implications for the treatment of IBD patients.http://dx.doi.org/10.1155/2015/434825 |
| spellingShingle | Misbah Misdaq Sonia Ziegler Nicolas von Ahsen Michael Oellerich Abdul R. Asif Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach Mediators of Inflammation |
| title | Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach |
| title_full | Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach |
| title_fullStr | Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach |
| title_full_unstemmed | Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach |
| title_short | Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach |
| title_sort | thiopurines induce oxidative stress in t lymphocytes a proteomic approach |
| url | http://dx.doi.org/10.1155/2015/434825 |
| work_keys_str_mv | AT misbahmisdaq thiopurinesinduceoxidativestressintlymphocytesaproteomicapproach AT soniaziegler thiopurinesinduceoxidativestressintlymphocytesaproteomicapproach AT nicolasvonahsen thiopurinesinduceoxidativestressintlymphocytesaproteomicapproach AT michaeloellerich thiopurinesinduceoxidativestressintlymphocytesaproteomicapproach AT abdulrasif thiopurinesinduceoxidativestressintlymphocytesaproteomicapproach |