Cxcl16

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 (see figure) 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. Some chemokines have a pro-inflammatory effect, others have a regulatory effect on the development and homeostasis of tissues.

CXCL16, also known as CXC-motif chemokine 16, or "scavenger receptor for phosphatidylserine and oxidized low density lipoprotein" is a small, human, chemotactically active, transmembrane cytokine that belongs to the group of CXC-motif chemokines. The coding gene is located on chromosome 17 in humans.

CXCL16 is produced by dendritic cells from lymphatic organs. Furthermore by (tumour-associated) T-cells, keratinocytes, bronchiogenic epithelial cells, smooth muscle cells, fibroblasts as well as various tumour cells.

CXCL16 is composed of a CXC chemokine domain, a transmembrane segment and a cytoplasmic protein portion. Unusual for a chemokine is its ability to be expressed both in a cell-bound and in a soluble form.

CXCL16, induced by the inflammatory cytokines interferon-gamma and TNF-alpha, binds exclusively to the CXCR6 chemokine receptor (also known as "bonzo") and affects different subgroups of T cells and NK cells. CXCL16 can be removed from the surface of expressing cells by the activity of metalloproteinase (ADAM10). Its binding to its receptor can be rapidly released by the activity of the enzyme ADAM17.

Increased chemokine expression is found in chronic inflammatory diseases such as HIV infection, atopic eczema, bronchial asthma, allergic rhinitis and psoriasis vulgaris. Chemokines play a positive role e.g. in wound healing, haematopoiesis (blood formation) or the defence against infections. The fact that chemokine receptors are present not only on inflammatory cells but also on tumor cells and endothelial cells suggests that they are also involved in the migration of tumor cells or the metastatic behavior of the various tumors.

CXCR6 appears to play a role as a "lung homing" receptor. CXCL16 is expressed to a significant extent by alveolar macrophages, bronchial epithelia, bronchiogenic smooth muscle cells and fibroblasts.

Keratinocytes: Keratinocytes stimulated by TNF-alpha interleukin-1α of interferon gamma produce relevant amounts of CXCL16. These CXCL16 concentrations have been shown to have significant antimicrobial activity against Staphylococcus aureus and Escherichia coli.

Arteriosclerosis/myocardial infarction: CXCL16 seems to play a pathogenetic role in the development of arteriosclerosis, among other chemokines. The chemokine is expressed in atherosclerotic palques. During acute cardiovascular events, soluble CXCL16 is upregulated in serum and could be considered as a biomarker for myocardial infarction in present serial studies.

Fibroblasts: In rheumatoid arthritis there is activity related (compared to healthy subjects) synovial overexpression of CXCL16, CXCR6, and RANKL. Anulus fibrosus cells express relevant amounts of CXCL16 after their activation

Arteriosclerosis/myocardial infarction: CXCL16 appears to play a pathogenetic role in the development of arteriosclerosis, among other chemokines. The chemokine is expressed in atherosclerotic palques. During acute cardiovascular events, soluble CXCL16 is upregulated in serum and could be considered as a biomarker for myocardial infarction in present serial studies.

Tumor-associated expressions: CXCL16 and CXCR6 are coexpressed on prostate cancer cells and tumor-associated T cells. The levels of expression of CXCL16 and CXCR6 correlated with a poor prognosis of the carcinoma.

Further tumour-associated overexpressions are detectable in bronchial carcinoma (C34.9), in colorectal carcinoma (C19.-) in carcinoma of the urinary bladder (C67.-).

In the case of breast carcinoma (C25.9), overexpression of cellular CXCL16 leads to suppression of invasion and metastasis of the tumour, so that this chemokine is discussed as a possible therapeutic principle.

The administration of folic acid accelerates the methylation of CXCL16, resulting in larger amounts of methylated CXCL16 gene promoters in colon, ileum and lung with an accumulation of so-called "invariant NK cells (iNKT cells)".

1. Day C et al (2009) The chemokine CXCL16 is highly and constitutively expressed by human bronchial epithelial cells. Exp Lung Res 35:272-283.
2. Fang Y et al.(2014) Chemokine CXCL16 expression suppresses migration and invasiveness and induces apoptosis in breast cancer cells. Mediators Inflamm 2014:478641.
3. Hu W et al (2014) CXCL16 and CXCR6 are coexpressed in human lung cancer in vivo and mediate the invasion of lung cancer cell lines in vitro. PLoS One 9:e99056.
4. Kee JY et al (2014) CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages. BMC Cancer 14:949.
5. Lee JT et al (2013) Expression analysis and clinical significance of CXCL16/CXCR6 in patients with bladder cancer. Oncol Lett 5:229-235.
6. Ludwig A et al (2007) Transmembrane chemokines: versatile 'special agents' in vascular inflammation. Thromb haemost 97:694-703.
7. Tohyama M et al (2007) CXCL16 is a novel mediator of the innate immunity of epidermal keratinocytes. Int Immunol 19: 1095-1102.