Cxcl12

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, in the CXC-chemokines they are separated by 1 (see figure), 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.

CXCL12, also C-X-C motif chemokine 12 or is a small, chemokine from the group of CXC chemokines, which plays a broad role in physiological (e.g. organogenesis) and pathological (oncogenesis, wound healing, inflammation) processes. The highly conserved chemokine is encoded by the CXCL12 gene, which is located on chromosome 10 q11 in humans. Several isoforms of CXCL12 are known. The functions of SDF-1alpha and SDF-1beta isoforms are best studied.

CXCL12 binds to 2 different chemokine receptors, CXCR4 and CXCR7. These receptors belong to the family of transmembrane, G-protein coupled chemokine receptors (see figure).

Organogenesis: Animal experiments have shown the essential role of CXCL12 in physiological developmental processes, such as organogenesis. In knockout mice lacking CXCL12 or the receptor CXCR4, severe organ damage occurs.

Angiogenesis: CXCL12 plays an important role in (inflammatory or oncogenic induced) angiogenesis.

Inflammation: In inflammatory tissues, increased expression of CXCL12 can be associated with a chemotactic effect on CXCR4-expressing lymphocytes. Animal experiments have shown that CXCL12 (syn: Angiogenic Chemokine Stromal Cell-derived Factor-1) and the associated CXCR4 receptor are upregulated in a psoriasis-like inflammation model, and CXCR4 receptor blockade significantly reduces these effects.

Oncogenic functions: Numerous tumors express the CXCL12 receptors CXCR4 or CXCR7. In these tumor cell lines, CXCL12 shows a chemotactic and growth-promoting effect. The chemotactic effect of CXCL12 on CXCR4-expressing tumor cell lines promotes the formation of metastases in organs with a high CXCL12 production rate (e.g. bone marrow, lung and liver). CXCL12 and its receptor CXCR4 are involved in the progression of ovarian and pancreatic cancer. Antagonists of the CXCR4 receptor are able to suppress tumor growth in animal experiments.

Viral infections: CXCL12 exerts an inhibitory effect on HI viruses. This is attributed to a CXCL12-induced "internalization" of the CXCR4 receptor. Remark: CXCR4 serves as a co-receptor in the docking of HIV-1 to the target cell.

Atherosclerosis: CXCR4(+) cells continuously accumulate in atherosclerotic plaques during plaque growth. Functional CXCR4 blockade leads to progressive plaque expansion with progression of the atherosclerotic process.

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4. Gil M et al (2014) CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells. J Immunol 193:5327-5337.
5. Zgraggen S et al(2014) An important role of the SDF-1/CXCR4 axis in chronic skin inflammation. PLoS One. 2014 Apr 2;9(4):e93665.