CXCL10 Activities, Biological Structure, and Source Along with Its Significant Role Played in Pathophysiology of Type I Diabetes Mellitus

Abstract

The etiology of the most autoimmune disorders is largely yet to be understood. However, major target antigens have been determined against some of clinically important molecules of human autoimmune diseases, such as insulin in type 1 diabetes mellitus (T1DM). T1DM is believed to be resulted from immune-mediated destruction of insulin-producing β-cells in pancreatic islets of Langerhans. Chemokines are small glycoproteins (weighing 8-10 kDa) that are chemotactive for a wide variety of cell types especially immune system cells and their target cells express appropriate G protein receptors. CXCL10 is a 10-kDa protein and is functionally categorized as an "inflammatory" chemokine. Recently, accumulating reports have shown that the serum and/or the tissue expressions of CXCL10 are increased in various autoimmune diseases like T1DM. Thus, in this article we will focus on the crucial role(s) played by CXCL10 in pathogenesis of T1DM. Therefore, we tried our best to collect the current reports regarding relationship between the serum concentrations of CXCL10 in T1DM.

The Biological Functions, Structure and Sources of CXCL10 and Its Outstanding Part in the Pathophysiology of Multiple Sclerosis

“…However, an identification of the structural properties and mechanism of action of CXCL10 needs to be made if CXCL10 is to be used as a worthwhile therapeutic target for treatment of the aforementioned pathological conditions. CXCL10 was initially identified in human U937 cells (a histiocytic lymphoma cell line with monocytic characterization and origin) and from human placenta and spleen as an IFN-γ-inducible product [30]; mob-1 and crg-2 are the rat and mouse homologs of human chemokine CXCL10, and they share 70 and 78% amino acid homology with these proteins, respectively [31]. Like other members of the chemokine subfamily, CXCL10 is a small-molecular-weight protein (10 kDa) which was functionally described as an ‘inflammatory' chemokine.…”

“…External stimuli which affect CXCL10 and the intracellular events leading to its expression (adopted from Ahmadi et al [30]). Signals are initiated by receptor-ligand interaction, either involving growth factors or cytokines, and stress stimuli are illustrated.…”

“…Additionally, CXCL10 is reported to act as an antiangiogenic/antitumor protein [37,38]. Although the precise biological functions of CXCL10 are yet to be completely identified, several lines of evidence have demonstrated that this chemokine is involved in the following physiological and pathological situations: (a) chemoattraction of macrophages, monocytes and activated T and NK cells [39,40,41]; (b) modulation of T cell development and function [42,43]; (c) inhibition of in vitro colony formation by early human bone marrow progenitor cells [44]; (d) stimulation of T cell adhesion to endothelial cells [45]; (e) induction of NK cell migration along with NK cell-mediated cytolysis; (f) in antiangiogenesis (including antitumor angiogenesis) [24,30,46], and (g) by mitogenic and chemotactic effects on vascular smooth muscle cells [43,44]. …”

“…This regulatory region of the CXCL10 gene contains motifs for a variety of signal transduction pathways including HS IFN-γ and NF-κB response elements [63,64 ](fig. 1) [30]. …”

Are mast cells important in diabetes?

“…The over-expression of MHC class-1 antigens leads to the production of several chemokines including RANTES and MCP-1 that attract MCs and other immune cells, which can be deleterious for the pancreatic β cells [19]. We previously reported that RANTES and MCP-1, which are part of the chemokine supergene family (8-to 10-kD proteins) inducible in a number of pathophysiologic processes, intradermally injected (10 ng/50 μl subcutaneously in the abdominal skin of rat) produce a strong inflammatory reaction, due to the recruitment of mast cells, showing that these chemokines are potent pro-inflammatory proteins with specific chemoattraction on inflammatory MCs [20].…”