Expression profiling and Ingenuity biological function analyses of interleukin-6- versus nerve growth factor-stimulated PC12 cells
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- 作者：Dieter Kunz (1)
Gaby Walker (2)
Marc Bedoucha (3)
Ulrich Certa (4)
Pia M?rz-Weiss (2)
Beatrice Dimitriades-Schmutz (1)
Uwe Otten (1) - 刊名：BMC Genomics
- 出版年：2009
- 出版时间：December 2009
- 年：2009
- 卷：10
- 期：1
- 全文大小：1588KB
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Gaby Walker (2)
Marc Bedoucha (3)
Ulrich Certa (4)
Pia M?rz-Weiss (2)
Beatrice Dimitriades-Schmutz (1)
Uwe Otten (1)
1. Department of Biomedicine, Institute of Physiology, University of Basel, Pestalozzistrasse 25, CH-4056, Basel, Switzerland
2. Molecular Medicine Laboratories (MML), Hoffmann-La Roche Ltd., Grenzacherstrasse 2, CH-4002, Basel, Switzerland
3. Discovery Research (PRBD), Hoffmann-La Roche Ltd., Grenzacherstrasse 2, CH-4002, Basel, Switzerland
4. Non-Clinical Drug Safety (NCS), Hoffmann-La Roche Ltd., Grenzacherstrasse 2, CH-4002, Basel, Switzerland
文摘
Background The major goal of the study was to compare the genetic programs utilized by the neuropoietic cytokine Interleukin-6 (IL-6) and the neurotrophin (NT) Nerve Growth Factor (NGF) for neuronal differentiation. Results The designer cytokine Hyper-IL-6 in which IL-6 is covalently linked to its soluble receptor s-IL-6R as well as NGF were used to stimulate PC12 cells for 24 hours. Changes in gene expression levels were monitored using Affymetrix GeneChip technology. We found different expression for 130 genes in IL-6- and 102 genes in NGF-treated PC12 cells as compared to unstimulated controls. The gene set shared by both stimuli comprises only 16 genes. A key step is upregulation of growth factors and functionally related external molecules known to play important roles in neuronal differentiation. In particular, IL-6 enhances gene expression of regenerating islet-derived 3 alpha (REG3A; 1084-fold), regenerating islet-derived 3 beta (REG3B/PAPI; 672-fold), growth differentiation factor 15 (GDF15; 80-fold), platelet-derived growth factor alpha (PDGFA; 69-fold), growth hormone releasing hormone (GHRH; 30-fold), adenylate cyclase activating polypeptide (PACAP; 20-fold) and hepatocyte growth factor (HGF; 5-fold). NGF recruits GDF15 (131-fold), transforming growth factor beta 1 (TGFB1; 101-fold) and brain-derived neurotrophic factor (BDNF; 89-fold). Both stimuli activate growth-associated protein 43 (GAP-43) indicating that PC12 cells undergo substantial neuronal differentiation. Moreover, IL-6 activates the transcription factors retinoic acid receptor alpha (RARA; 20-fold) and early growth response 1 (Egr1/Zif268; 3-fold) known to play key roles in neuronal differentiation. Ingenuity biological function analysis revealed that completely different repertoires of molecules are recruited to exert the same biological functions in neuronal differentiation. Major sub-categories include cellular growth and differentiation, cell migration, chemotaxis, cell adhesion, small molecule biochemistry aiming at changing intracellular concentrations of second messengers such as Ca2+ and cAMP as well as expression of enzymes involved in posttranslational modification of proteins. Conclusion The current data provide novel candidate genes involved in neuronal differentiation, notably for the neuropoietic cytokine IL-6. Our findings may also have impact on the clinical treatment of peripheral nerve injury. Local application of a designer cytokine such as H-IL-6 with drastically enhanced bioactivity in combination with NTs may generate a potent reparative microenvironment.