CXCL10

Chemokines, a subgroup of cytokines, are small (size between 8 and 10 kDa), chemotactically active proteins (signal proteins). They are common in all vertebrates, some virus types and bacteria. In humans, about 50 chemokines are currently known. A strongly conserved structural feature of all chemokines is a fixed group of cysteine residues that is stabilized by 1 or 2 disulfide bridges. This key structural position in the molecule is responsible for its fixed 3-dimensional structure (see below chemokines).

In the CC-chemokines the cysteines follow each other directly (see figure), in the CXC-chemokines they are separated by 1, in the CXXXC-chemokines by 3 other amino acids. Chemokines are produced and secreted by a large number of immune cells. They mediate their signals by means of specific chemokine receptors via G-proteins. The fact that chemokines and their receptors are not only expressed on inflammatory cells, but also by epithelial cells, mesenchymal cells, neurogenic cells, endothelial cells, and various tumor cell lines, suggests that they participate in numerous regulatory cell functions.

CXCL10, also known as C-X-C motif chemokine 10 or P-10, is a small inflammatory chemokine consisting of 98 amino acids from the group of CXC chemokines, which is formed and secreted by different cell systems (mainly by gamma interferon but also triggered by other cytokines).

The chemokine is encoded by the CXCL10 gene, which in humans is located on chromosome 4q21.1 together with the genes for CXCL9 and CXCL11. Like the homologous chemokines CXCL9 and CXCL11, CXCL10 binds to the G-protein-coupled chemokine receptor CXCR3 and has a chemotactic effect on T cells but not on neutrophil granulocytes. The CXCR3 receptor is also expressed in pneumocytes and pulmonary and hepatic fibroblasts. A variant of the CXCR3 receptor has been described, which has been named CXCR3-B (the previously known CXCL3 receptor is to be renamed CXCL3A in the future). CXCL3B mediates the angiostatic activity of CXCR3 ligands and also acts as a functional receptor for CXCL4.

CXCL10 is secreted by numerous cells including monocytes, neutrophil granulocytes, endothelial cells, keratinocytes, mesenchymal cells, dendritic cells, hepatocytes, astrocytes and fibroblasts. The chemokine acts as an attractor for monocytes/macrophages, T cells, NK cells, eosinophil granulocytes and dendritic cells. It is involved in antitumor activities, in the inhibition of neoangiogenesis and bone marrow proliferation.

Hepatitis C: Plasma levels of CXCL10 are elevated in patients with untreated chronic hepatitis C virus (HCV) genotype 1 or 4 infection.

Multiple Sclerosis: It has been shown that the CXCL10/CXCR3 axis is upregulated in relapsing-remitting MS. In a 1-year therapy study with natalizumab it was shown that the proinflammatory cytokines such as: Interleukin-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α together with the chemokines CXCL9, CXCL10, CXCL11, CCL17 and CCL22 were significantly decreased. From these results, clear relationships can be deduced between the extent of cytokine expression and the activity level of MS. Such correlations are not to be interpreted as disease-specific, but are also to be expected in other TH1-associated inflammations.

Heart failure and left ventricular dysfunction: CXCL10 and the homologous chemokines CXCL-9 and CXCL-11 have been shown to be valid biomarkers for the development of heart failure and left ventricular dysfunction.

Rheumatoid Arthritis: Chemokines (CXCL) and their receptors play an important role in the pathogenesis of rheumatoid arthritis (RA). In one study it was shown that "Single nucleotide polymorphisms -SNPs- in the CXCL10 gene (rs8878 A>G) but not in the CXCL9 gene are associated with rheumatoid arthritis.

Kotrych D et al (2015) CXCL9 and CXCL10 gene polymorphisms in patients with rheumatoid arthritis. Rheumatol Int 35:1319-1323.

Lagging M et al (2006) IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection. Hepatology 44: 1617-1625.

Liang Y et al (2017) Serum Monokine Induced by Gamma Interferon Is Associated With Severity of Coronary Artery Disease. Int Heart J 58:24-29.

Ohmori Y et al. (1995) The interferon-stimulated response element and a κB site mediate synergistic induction of murine IP-10 gene transcription by IFN-γ and TNF-α. J Immunol 154:5235-5244.

Ohtani H et al (2009) Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric carcinoma. J path 217:21-31.

Vazirinejad R et al.(2014) The Biological Functions, Structure and Sources of CXCL10 and Its Outstanding Part in the Pathophysiology of Multiple Sclerosis Neuroimmunomodulation 21: 322-330