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Induction of CXCL1 by Extracellular Matrix and Autocrine Enhancement by Interleukin-1 in Rat Pancreatic β-Cells

Department of Genetic Medicine and Development (P.R., N.L.-M., E.H., J.-C.I., P.A.H.) and Cellular Physiology and Metabolism (F.C.), University Medical Center, 1211 Geneva, Switzerland; and Division of Endocrinology and Diabetes (J.A.E., M.B.-S., M.Y.D.), University Hospital of Zürich, 8091 Zürich, Switzerland

Address all correspondence and requests for reprints to: Dr. Pascale Ribaux, Department of Genetic Medicine and Development, University Medical Center, 1 Michel-Servet Street, 1211 Geneva-4, Switzerland. E-mail: Pascale.Ribaux{at}medecine.unige.ch.

As we showed previously, the extracellular matrix (ECM) derived from rat bladder carcinoma cells (804G-ECM) has positive effects on rat primary β-cell function and survival in vitro. The aim of this study was to define β-cell genes induced by this ECM with a specific focus on cytokines. Analysis of differential gene expression by oligonucleotide microarrays, RT-PCR, and in situ hybridization was performed to identify cytokine mRNA induced by this matrix. Four cytokines were overexpressed on 804G-ECM compared with poly-L-lysine: C-X-C motif ligand 1 (CXCL1), CXCL2, interferon-inducible protein-10, and IL-1β. A time-course experiment indicated that maximal induction by 804G-ECM of CXCL1/2 and interferon-inducible protein-10 occurred at 4 h. Stimulation of CXCL1 release by β-cells on 804G-ECM was confirmed at the protein level. Moreover, secreted CXCL1 was shown to be functionally active by attracting rat granulocytes. Preventing the interaction of β1 integrins and laminin-5 (a major component of 804G-ECM) with specific antibodies resulted in a 40–50% inhibition of CXCL1 expression. Using the nuclear factor-B pathway inhibitor Bay 11–7082 it is demonstrated that CXCL1 expression and secretion are dependent on nuclear factor-B activation. IL-1 secreted by β-cells plated on 804G-ECM was found to be a key soluble mediator because treatment of cells with the IL-1 receptor antagonist significantly reduced both CXCL1 gene expression and secretion. It is concluded that ECM induces expression of cytokines including CXCL1 with amplification by IL-1 acting via a positive autocrine feedback loop.

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