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Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Chandrasekar, Bysani Srinivas Mummidi Mestril, Ruben Nemer, Mona |
| Copyright Year | 2005 |
| Abstract | In patients with congestive heart failure, high serum levels of the proinflammatory cytokine interleukin (IL)-18 were reported. A positive correlation was described between serum IL-18 levels and the disease severity. IL-18 has also been shown to induce atrial natriuretic factor (ANF) gene expression in adult cardiomyocytes. Because re-expression of the fetal gene ANF is mostly associated with hypertrophy, a hallmark of heart failure, we hypothesized that IL-18 induces cardiomyocyte hypertrophy. Treatment of the cardiomyocyte cell line HL-1 with IL-18 induced hypertrophy as characterized by increases in protein synthesis, phosphorylated p70 S6 kinase, and ribosomal S6 protein levels as well as cell surface area. Furthermore, IL-18 induced ANF gene transcription in a time-dependent manner as evidenced by increased ANF secretion and ANF promoter-driven reporter gene activity. Investigation into possible signal transduction pathways mediating IL-18 effects revealed that IL-18 activates phosphoinositide 3-kinase (PI3K), an effect that was blocked by wortmannin and LY-294002. IL-18 induced Akt phosphorylation and stimulated its activity, effects that were abolished by Akt inhibitor or knockdown. IL-18 stimulated GATA4 DNA binding activity and increased transcription of a reporter gene driven by multimerized GATA4-binding DNA elements. Pharmacological inhibition or knockdown studies revealed that IL-18 induced cardiomyocyte hypertrophy and ANF gene transcription via PI3K, PDK1, Akt, and GATA4. Most importantly, IL-18 induced ANF gene transcription and hypertrophy of neonatal rat ventricular myocytes via PI3K-, Akt-, and GATA4-dependent signaling. Together these data provide the first evidence that IL-18 induces cardiomyocyte hypertrophy via PI3K-dependent signaling, defines a mechanism of IL-18-mediated ANF gene transcription, and further supports a role for IL-18 in inflammatory heart diseases including heart failure. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://medschool.lsuhsc.edu/biochemistry/docs/chandrasekar%20jbc%20paper%202005.pdf |
| PubMed reference number | 15574430v1 |
| Volume Number | 280 |
| Issue Number | 6 |
| Journal | The Journal of biological chemistry |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-Phosphatidylinositol 3-Kinase 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase Atrial Natriuretic Factor F Factor GATA4 gene Gene Expression Heart Atrium Heart Diseases Heart failure Hypertrophic disorder of skin, unspecified Hypertrophy Interleukins LY 294002 Muscle Cells Myocytes, Cardiac Natriuretic Hormones Patients Phosphatidylinositols Protein Biosynthesis Proto-Oncogene Proteins c-akt Recombinant Interleukin-18 Ribosomal Protein S6 Kinase Ribosomal Protein S6 Kinases, 70-kDa Signal Transduction Pathways Transcription, Genetic cytokine dna binding wortmannin |
| Content Type | Text |
| Resource Type | Article |
