## 3 Transcriptional Regulation of Individual Chemokine Genes in Pancreatic \(\beta\)-Cells
### Chemokine C-X-C Motif Ligands 1 and 2 (CXCL1/CXCL2)  
Rodent and human islets and pancreatic \(\beta\)-cell lines all markedly upregulate CXCR2 ligands (e.g., CXCL1, CXCL2, _etc._) in response to inflammatory signals [13,16]. Moreover, circulating CXCL1 is elevated in human T1 DM [38], obese rodents [59], and human subjects with T2 DM [37]. Islets from obese mice [11] and mice transgenic for hIAPP [57] also have higher expression of CXCL1 relative to their control counterparts. Both local and systemic CXCL1 bind to the CXCR2 receptor, which is highly abundant on neutrophils. CXCR2 likely participates in, or directly controls, neutrophil recruitment and the associated inflammation-mediated destruction of pancreatic islet \(\beta\)-cells [60,61]. Indeed, systemic delivery of compounds that inhibit the activity of the receptors CXCR1 and CXCR2 augments islet graft function after transplantation [61], and protects against autoimmune forms of diabetes in mice [60]. These findings implicate CXCR1\({}^{+}\) and CXCR2\({}^{+}\) immune cells (e.g., neutrophils) as major contributors to the process of islet \(\beta\)-cell destruction. In addition, pharmaceutical targeting of CXCR2 for several other inflammatory diseases is currently being considered [62, 63, 64]. In pancreatic \(\beta\)-cells, the genes encoding CXCL1 and CXCL2, which are both ligands for CXCR2, are strongly and rapidly regulated by signals that activate NF-\(\kappa\)B [16]. In clonal \(\beta\)-cell lines, rat islets and human islets, CXCL1 and CXCL2 are primary response genes (_i.e._, they are activated rapidly in a manner that does not require new protein synthesis). Despite the presence of sites recognized by STAT1 transcription factors, the CXCL1 and CXCL2 genes do not respond to IFN-\(\gamma\) alone as a transcriptional activation signal. Instead, these genes use STAT1 as an accessory factor to support the transcriptional response induced by IL-1\(\beta\) activation of the NF-\(\kappa\)B p65 and p50 heterodimer [16]. While the increase in transcription of the CXCL1 and CXCL2 genes in response to IL-1\(\beta\) is blocked by inhibition of IKK\(\beta\), interfering with the p38 MAPK has no effect [16]. In addition, specific covalent modifications to histone H3 within the core promoter of the CXCL1 and CXCL2 genes are produced upon \(\beta\)-cell exposure to IL-1\(\beta\). These include increased acetylation of Lys14 and methylation of Lys4 and decreased methylation of both Lys9 and Lys27 [16]. These coordinated alterations in histone chemical modifications correlate with an increase in Ser5 phosphorylation of RNA polymerase II (Pol II) carboxy terminal domain (CTD) within the core promoter of the CXCL1 and CXCL2 genes. Furthermore, phosphorylation of Ser2 within the RNA Pol II CTD is enhanced on the coding region of the CXCL1 and CXCL2 genes after cellular exposure to IL-1\(\beta\), consistent with elongation of transcription. Taken together, the post-translational modifications to RNA Pol II are congruent with the appearance of transcripts encoding chemokines within 1 h after IL-1\(\beta\) stimulation and an increase in chemokine protein secretion by 3 h [16]. The CXCL1 and CXCL2 proteins have potent biological effects on human peripheral blood neutrophils, which include increased migration and alterations in cell surface integrin expression. Human neutrophils increase their surface expression of the integrins Cd11b and Cd11c, but not Cd11a, after exposure to either CXCL1 or CXCL2 [16]. The combination of both chemokines is redundant in this context. The pathophysiological significance of these findings is postulated to be as follows: islet \(\beta\)-cells exposed to cytokines, such as IL-1, synthesize micromolar levels of nitric oxide (NO\(\bullet\)) [31, 32, 33, 34] while concurrently synthesizing and secreting ligands that chemoattractant neutrophils. CXCR2 activation by CXCL1 or CXCL2 enhances neutrophil integrin expression, which allows for neutrophil adherence to endothelial cells to facilitate migration into inflammatory sites.