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The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

ABSTRACT: Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) commonly used for the treatment of arthritis and chronic pain associated with musculoskeletal injuries. However, its use is associated with a variety of adverse drug reaction, including rare but severe hepato- and nephrotoxicity. The molecular mechanism leading to diclofenac induced immunoallergic hepatitis is unknown. The objective of this study is to identify the molecular mechanisms involving immune mediated inflammatory reactions and its link to DILI through whole genome gene expression profiling.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE100036 | GEO | 2019/06/30

REPOSITORIES: GEO

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Project description:Acute myeloid leukemia is a heterogeneous disease with regard to the underlying genetic and molecular pathophysiology. Non-steroidal anti-inflammatory drugs (NSAIDs) exert significant anti-proliferative effects in various malignant cells in vitro and in vivo. Hence, these agents can be utilized to study potential disease specific anti-proliferative pathways. In this study, a total number of 42 bone marrow derived CD34+ cells from de novo AML patients and the AML cell lines THP-1 and HL-60 were treated with the NSAIDs Sulindac sulfide and Diclofenac. We examined viability, apoptosis, differentiation and addressed the molecular mechanisms involved. We found a consistent induction of apoptosis and to some extent myeloid differentiation in NSAID treated AML cells. Comprehensive protein and gene expression profiling of Diclofenac treated AML cells revealed transcriptional activation of GADD45M-NM-1 and its downstream MAPK/JNK pathway as well as increased protein levels of the Caspase-3 precursor. This points towards a role of the c-Jun NH2-terminal kinase (JNK) in NSAID mediated apoptosis. This was dependent on JNK activity as addition of a specific JNK-inhibitor abrogated apoptosis. Furthermore, the AP-1 transcription factor family membersM-bM-^@M-^Y c-Jun, JunB and Fra-2 were transcriptionally activated in NSAID treated AML cells. Re-expression of these transcription factors led to activation of GADD45M-NM-1 with induction of apoptosis. Mechanistically, we demonstrate that NSAIDs induce apoptosis in AML through a novel pathway involving increased expression of AP-1 heterodimers, which by itself is sufficient to induce GADD45M-NM-1 expression with consecutive activation of JNK and induction of apoptosis. HL-60 and THP-1 AML cells were treated with 100 M-BM-5M Diclofenac or DMSO as control for 48 hours. Each experiment was performed in duplicate. After this treatment total RNA of the cells was harvested and analysed by means of gene expression profiling with the Affymetrix HU-133A array.

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The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

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