Chemokines/chemoattractant cytokines are small proteins with a mass of 8–10 kDa. Cytokines and chemokines are effector molecules that play a pivotal role in orchestrating both the innate and acquired immune responses. Additionally, they are involved in cell differentiation, division, and repair. The chemokine’s nomenclature has been established in the early 1990s at the International Symposium on Chemotactic Cytokines in Baden (Lindley et al. 1993) on the base of the N-term conserved cysteine motif. Chemokines are classified into four families: C, CC, CXC, CX3C, where X represent any amino acid residue. CXCL10, also called interferon-γ-inducible protein 10 (IP-10), has been initially identified as a chemokine induced by interferon-γ and secreted by a variety of tissues, for example, endothelial cells, monocytes, fibroblasts, and keratinocytes (Luster and Ravetch 1987). CXCL10 has been classified as inflammatory chemokine due to its ability to strongly attract lymphocytes, lack of the ELR motif (glutamic acid-leucine-arginine) which abolishes neovascularization, and function as angiostatic chemokine (Strieter et al. 1995). CXCL10 as well as CXCL9 (MIG) and CXCL11 (ITAC) exerts its action of immune response activator through its natural receptor CXCR3, but CXCL10 also binds to a member of the Toll-like receptor family, TLR4, shown in pancreatic β-cells (Schulthess, Paroni et al. 2009). Over the past few years, both serum levels and tissue expression of CXCL10 were monitored and correlated with various autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, autoimmune thyroid disease, and diabetes mellitus (Hanaoka et al. 2003; Rotondi et al. 2007). Diabetes is a metabolic disease in which the body is unable to produce sufficient amounts of insulin to maintain normoglycemia. Diabetes was reported by Greek physicians already in 250 B.C. and is the Greek word for “syphon,” referring to the severe condition of polyuria, the production of large amounts of urine. The complete term “diabetes mellitus” was established later in the seventeenth century. Mellitus is Latin for honey, which is how the physician Thomas Willis described the taste of urine in patients.
CXCL10 in T1DM
CXCL10 in Virus-Mediated Diabetes
Basic and still unresolved questions regarding the onset of diabetes are how endogenous β-cell antigens become immunogenic and whether environmental factors such as viruses play a causative role in this process. Infection with viruses with a tropism for pancreatic islets highly increases CXCL10 levels both in vivo and in vitro. Mouse studies suggest a pivotal role of CXCL10 during virus-induced diabetes (Christen et al. 2003; Morimoto et al. 2004). Abolishing CXCL10 signaling using specific antibodies leads to a reduction of diabetes incidence (Morimoto et al. 2004). The reduction of diabetes incidence in mice is rather chemokine-specific than a redundant immune system effect. The protective effect is due to less lymphocyte infiltration combined with a reduction of CD8+ lymphocyte activation. In contrast, CXCL10 expression in mice is insufficient to trigger significant autoimmune damage of β-cells. CXCL10 was able to abrogate autoimmunity when it was expressed outside the pancreas (Christen and Von Herrath 2004).
CXCL10 in T2DM
Recently, the presence of immune cell infiltration within islets was also observed in T2DM (Ehses et al. 2007); elevated levels of cytokines in the serum and within islets and apoptotic β-cells characterize the disease. High serum levels of the chemokine CXCL10 have been found in patients with manifest T2DM and with a high risk to develop the disease (Nicoletti et al. 2002; Xu et al. 2005; Herder et al. 2006). CXCL10 does not only act as chemoattractant for the immune system but also triggers β-cell apoptosis in isolated human islets (Schulthess et al. 2009). CXCL10 expression was observed in islets in diabetes as well as in islets from obese patients (Schulthess et al. 2009) and in high-fat diet-fed mice (unpublished observation). Also in adipose tissue from obese individuals (Herder et al. 2007a) and obese mice, CXCL10 is increased.
There is strong evidence that CXCL10 plays a causative role for the onset and development of diabetes. However, serum levels of CXCL10 during the development of the disease are discordant among studies. Such discrepancy can be produced by limitation of the analysis as well as the comparison groups (sex, age and especially duration of the autoimmune disease). Serum levels of CXCL10 may not reflect its expression within the islet of Langerhans, observed in obesity, T1DM and T2DM. Different tissue vascularization and time and duration of CXCL10 expression during the disease are important considerable variables. The dual effect of initiation/maintenance or abolition of the immune response and its relation to time and location of CXCL10 expression was already described in mice during virus-induced diabetes (Christen and Von Herrath 2004). Such a complex scenario is strengthening the role of CXCL10 during the onset of both T1DM and T2DM. Due to its potential role as diagnostic marker as well as its intriguing apoptotic activity, further studies are required in order to: (1) establish a consistent analysis method to bring uniformity in the results among different studies, (2) further elucidate the activation pathways that lead β-cells to undergo apoptosis upon CXCL10 signaling activation, and (3) clarify the extent of the contribution of CXCL10 in vivo during the onset of autoimmune disease.
This work was supported by the European Research Council (ERC), the German Research Foundation (DFG), and the Juvenile Diabetes Research Foundation (JDRF).
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