CXCL9

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

In CC chemokines, the cysteines follow each other directly (see Fig.), in CXC chemokines they are separated by 1, in CXXXC chemokines by 3 other amino acids. Chemokines are produced and secreted by a variety of immune cells. They mediate their signals by means of specific chemokine receptors via G-proteins.

The fact that chemokines and their receptors are expressed not only on inflammatory cells, but also by epithelial cells, mesenchymal cells, neurogenic cells, endothelial cells, also various tumor cell lines, suggests that they participate in numerous regulatory cell functions.

CXCL9, also called C-X-C motif chemokine 9 or "monokines induced by gamma interferon" or MIG , is a small 125 amino acid chemokine belonging to the group of CXC chemokines that is primarily induced by gamma interferon.

The chemokine is encoded by the CXCL9 gene, which in humans is located on chromosome 4q21.1 along with the genes for CXCL10 and CXCL11. CXCL, like the homologous chemokines CXCL10 and CXCL11, binds to the G protein-coupled chemokine receptor CXCR3 and has a chemotactic effect on T cells but not for neutrophil granulocytes.

The CXCR3 receptor is also expressed in pneumocytes and in pulmonary and hepatic fibroblasts. A variant of the CXCR3 receptor has been described, designated CXCR3-B (the previously known CXCR3 receptor will be named CXCR3A in the future). CXCR3B mediates the angiostatic activity of CXCR3 ligands and also acts as a functional receptor for CXCL4.

CXCL9 is further produced and secreted in dermal fibroblasts and venous endothelial cells. The induction can be enhanced by TNF-alpha.

The enzymes gelatinase B/matrix metalloproteinase 9 inhibit CXCL10 function by cleaving CXCL9 at 3 distinct sites in its extended carboxy-terminal region. In cultures of human microvascular endothelial cells, growth is inhibited by CXCL9, CXCL10, CXCL11, and CXCL4.

CXCL9 is a key immunoregulatory factor for versch. CXCL9 is a key immunoregulatory chemokine for various infections. For example, in patients with kidney transplants infected by polyomavirus BK, serum CXCL9 levels are significantly elevated.

Recent prospective studies of serum cytokines in patients with circumscritical scleroderma have identified potential blood markers of disease activity, including CXCL9 (Torok KS et al. 2019). However, the applicability of these markers in PRS/ECDS patients is unclear, and they are not yet widely available in clinical practice.

Heart failure and left ventricular dysfunction: CXCL9 and the homologous chemokines CXCL -10, -11 have been shown to be valid biomarkers for the development of heart failure and left ventricular dysfunction. Serum MIG levels (CXCL9) have been shown to be associated with the severity of coronary heart disease.

Psoriasis: In a larger study, serum levels of CXCL9, CCL5, osteopontin (OPN) were shown to be elevated in psoriatic patients compared to a healthy control group. These findings were independent of the degree of obesity of the patients.

GVHD: Serum levels of CXCL9 are elevated in GVHD. CXCL9 could serve as a (however unspecific) biomarker for GVHD.

Liver cirrhosis and portal hypertension: CXCL9 and other chemokines play an important role in the pathogenesis of liver cirrhosis. CXCL9 is significantly increased in patients with liver cirrhosis and severe portal hypertension. CXCL9 levels are associated with a poor prognosis.

Malignancies: CXCL9 is also expressed in some malignant tumors.

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.

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3. Duarte GV et al (2015) Osteopontin, CCL5 and CXCL9 are independently associated with psoriasis, regardless of the presence of obesity. Cytokine 74:287-292.
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7. 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 .
8. 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 Pathol 217:21-31.

9. Torok KS et al (2019) Immunopathogenesis of pediatric localized scleroderma. Front Immunol 10:908.