## 3 Transcriptional Regulation of Individual Chemokine Genes in Pancreatic \(\beta\)-Cells
### Chemokine C-X-C Motif Ligand 10 (CXCL10)  
Because the mechanism(s) underlying antigen-specific leukocyte migration into the pancreatic islets is currently unknown, a systematic analysis of the expression and function of individual chemokines in response to pro-inflammatory cytokines, such as IL-1\(\beta\) and IFN-\(\gamma\), is an essential component for understanding islet inflammatory processes that lead to diabetes mellitus. The gene encoding CXCL10 is responsive to both IL-1\(\beta\) and IFN-\(\gamma\) in pancreatic \(\beta\)-cells, with synergistic expression when both cytokines are present [17]. The p65 and p50 subunits of NF-\(\kappa\)B are recruited to the \(\kappa\)B genomic response elements in the CXCL10 proximal gene promoter within 15 minutes after \(\beta\)-cell exposure to IL-1\(\beta\).  
IFN-\(\gamma\) is a key regulatory cytokine that participates in \(\beta\)-cell demise [67, 68] and induces both the expression and phosphorylation of STAT1 proteins [69]. STAT1\(a\) is a versatile regulator of various genes involved in \(\beta\)-cell death and dysfunction [70] and is one of the factors that potentiates the IL-1\(\beta\)-mediated induction of various genes in pancreatic \(\beta\)-cells [16, 17, 71, 72], including CXCL10. Circulating levels of CXCL10 are also elevated in T1 DM and T2 DM (Table 2). Therefore it is feasible that chemokine release from pancreatic \(\beta\)-cells, in response to pro-inflammatory signals, is a contributing factor to the observed increases in circulating chemokine levels.  
Analogous to what is observed for NF-\(\kappa\)B transcription factors in response to IL-1\(\beta\), STAT1 is also observed at ISE containing regions of the CXCL10 gene promoter after IFN-\(\gamma\) exposure. These responsescoincide with recruitment of the coactivators p300 and CBP [17]. Interfering with JAK signaling using a low molecular weight inhibitor prevents the cytokine-mediated increases in CXCL10 mRNA and promoter activity. In addition, adenoviral delivery of STAT1 with Phe substituted for Tyr at position 701 decreases gene activation and release of CXCL10 protein [17]. Interestingly, a replacement of Ser727 with either Ala or Thr has no effect on cytokine-mediated expression of the CXCL10 gene [17]. Moreover, and consistent with rapid upregulation of chemokine gene transcription by pro-inflammatory stimuli, _in vivo_ expression of a regulatory protein that blocks NF-kB transcriptional activity prevents insulitis and hyperglycemia that normally occurs in mice after injections of multiple low doses of streptozotocin. Part of the mechanism for this protection includes decreased expression of CXCL10 [21]. Thus, NF-kB and STAT1 cooperate to control the production of CXCL10 in pancreatic \(\beta\)-cells exposed to pro-inflammatory signals, which in turn influences immune cell activity within the pancreas.  
CXCL10 is closely associated with autoimmune-mediated diabetes [20,73], and the expression of the CXCL10 gene increases prior to onset of diabetes in NOD mice, a rodent model of autoimmunity [42]. The CXCR3 receptor, activated by multiple ligands including CXCL10, is present on T-lymphocytes [74]. CXCR3 is present on both CD4\({}^{+}\) and CD8\({}^{+}\) T-cell populations and is associated with a Th1 phenotype. Islet \(\beta\)-cells make CXCL10 under several distinct inflammatory conditions (Table 1). CD4\({}^{+}\) T-cells are found in pancreatic islets in both T1 DM and T2 DM [75] and are also present in the exocrine tissue of subjects with T1 DM [76]. CD8\({}^{+}\) T-cells are also present in islets of individuals with T1 DM [75]. Arrival of T-cells into pancreatic tissue before and during disease onset and progression may be due, at least in part, to chemokine molecules (e.g., CXCL10) released from \(\beta\)-cells after exposure to pro-inflammatory stimuli.