Disease relevance of CXCL16

• By quantitative RT-PCR and immunohistochemistry, we show that CXCL16 is highly expressed in human gliomas, while expression in normal brain is low and mainly restricted to brain vascular endothelial cells [1].
• Most importantly, CXCL16 increased cell-cell adhesion and induced kappa B-dependent ASMC proliferation, indicating that CXCL16 may play an important role in the development and progression of atherosclerotic vascular disease [2].
• In this study, we demonstrate that membrane-bound SR-PSOX/CXCL16 mediates adhesion and phagocytosis of both Gram-negative and Gram-positive bacteria [3].
• Experimental human endotoxemia (n = 6) led to an 8-fold increase in whole-blood CXCL16 messenger ribonucleic acid (p < 0.001) and a 1.7-fold increase in soluble (sol)-CXCL16 (p < 0.001), a cleaved active chemokine [4].
• Finally, antibody-mediated blocking of CXCL16 ameliorated experimental immune nephritis [5].
• Cultured schwannoma cells responded to CXCL16-stimulation by phosphorylation of kinases p42/44 (Erk 2/1) that could be inhibited by the MEK1/2-inhibitor U0126 indicating an involvement of the mitogen-activated protein kinase signal transduction pathway [6].

High impact information on CXCL16

• We describe a protein with the hallmarks of a chemokine, designated CXCL16, that is made by dendritic cells (DCs) in lymphoid organ T cell zones and by cells in the splenic red pulp [7].
• CXCL16 may function in promoting interactions between DCs and CD8 T cells and in guiding T cell movements in the splenic red pulp [7].
• CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway [8].
• METHODS: Expression of CXCL16 and CXCR6 was analyzed by immunohistochemistry, reverse transcription-polymerase chain reaction, Western blotting, and/or flow cytometry [9].
• Furthermore, anti-CXCL16 monoclonal antibody significantly reduced the clinical arthritis score and reduced infiltration of inflammatory cells and bone destruction in the synovium of mice with CIA [9].

Biological context of CXCL16

• CXCL16 signals via Gi, phosphatidylinositol 3-kinase, Akt, I kappa B kinase, and nuclear factor-kappa B and induces cell-cell adhesion and aortic smooth muscle cell proliferation [2].
• CXCL16 induced I kappa B phosphorylation and degradation [2].
• To dissect the biological and signal transduction pathways elicited by CXCL16, human aortic smooth muscle cells (HASMC) were treated with pharmacological inhibitors or transiently transfected with pathway-specific dominant-negative or kinase-dead expression vectors prior to the addition of CXCL16 [2].
• By transfection of human and murine CXCL16 in different cell lines, we show that soluble CXCL16 is constitutively generated by proteolytic cleavage of transmembrane CXCL16 resulting in reduced surface expression of the transmembrane molecule [10].
• CONCLUSION: The findings from this study have demonstrated for the first time that CXCR6 and CXCL16 are co-expressed by first-trimester human trophoblast cells and stimulate their proliferation and invasion in an autocrine/paracrine manner [11].

Anatomical context of CXCL16

• CXCL16 was also found in the thymic medulla and in some nonlymphoid tissues, indicating roles in thymocyte development and effector T cell trafficking [7].
• CXCL16 is expressed on the surface of APCs including subsets of CD19(+) B cells and CD14(+) monocyte/macrophages, and functional CXCL16 is also shed from macrophages [12].
• CXCR6 may also contribute to tissue localization of plasma cells through its direct binding to membrane-anchored CXCL16 [13].
• In vitro polarized T cell subsets including Th1, Th2, and Tr1 cells express functional Bonzo, suggesting expression of this receptor in chronic inflammation, which we further verified by demonstration of CXCL16-mediated migration of tonsil-derived CD4(+) T lymphocytes [12].
• CXCL16 is continuously released from glial cells by proteolytic cleavage which is rapidly enhanced by stimulation with phorbol-12-myristate-13-acetate (PMA) [1].

Associations of CXCL16 with chemical compounds

• All-trans retinoic acid regulates CXCL16/SR-PSOX expression [14].
• These findings suggest that retinoid signaling might be a pathway modulating inflammatory response by regulating CXCL16 expression in a cell-specific manner [14].
• Six genes were selected for confirmation by real-time PCR, and of these, CXCL16, ZNF331, JUN, and PF4 were the most significantly affected by benzene exposure, a finding that was confirmed in a larger data set from 28 subjects [15].
• CXCL16 is a unique chemokine with characteristics as a receptor for phosphatidylserine and oxidized low density lipoproteins in macrophages, and is involved in the accumulation of cellular cholesterol during atherosclerotic lesion development [16].
• While bacterial lipopolysaccharide (LPS) has been shown to stimulate CXCL16 expression in SMC, its effects on CXCR6 are not known [17].

Physical interactions of CXCL16

• CXCL16 on the cholangiocyte membrane was able to support lymphocyte adhesion by triggering conformational activation of beta(1) integrins and binding to VCAM-1 [18].

Regulatory relationships of CXCL16

• Functionally, recombinant soluble CXCL16 enhanced proliferation of CXCR6-positive murine astroglial and microglial cells [1].
• The constitutive shedding of CXCL16 from the endothelial cell surface is blocked by inhibitors of ADAM10 and is independent of additional inhibition of ADAM17 [10].
• RESULTS: CXCL16 was expressed in RA synovium [9].
• Furthermore, CXCL16 increased cell-cell adhesion and induced cellular proliferation in an NF-kappa B-dependent manner [2].

Other interactions of CXCL16

• As shown by inhibitor studies, two distinct members of the disintegrin-like metalloproteinase family ADAM10 and 17 are involved in the constitutive and PMA-induced shedding of glial CXCL16 [1].
• In addition, the constitutive cleavage of transfected human CXCL16 was markedly reduced in embryonic fibroblasts generated from ADAM10-deficient mice [10].
• Exposure of HASMC to CXCL16 increased NF-kappa B DNA binding activity, induced kappa B-driven luciferase activity, and up-regulated tumor necrosis factor-alpha expression in an NF-kappa B-dependent manner [2].
• The IFN-gamma induction of CXCL16 was also associated with increased uptake of oxLDL into these cells [19].
• RESULTS: CXCL16 was markedly elevated in RA synovial fluid (SF) samples, being as high as 145 ng/ml [8].

Analytical, diagnostic and therapeutic context of CXCL16

• The effect of anti-CXCL16 monoclonal antibody on murine collagen-induced arthritis (CIA) was evaluated [9].
• Using double-labelled immunohistochemistry, we identified that smooth muscle cells in human lesions express CXCL16 [19].
• We then examined the kinetic secretion of CXCL16 in the supernatant of primary-cultured trophoblast by enzyme-linked immunosorbent assay [11].
• Bronchoalveolar lavage (BAL) fluid from all subjects contained large amounts of CXCL16 [20].
• There were no significant correlations between CXCL16 levels and different measures of CAD severity determined by quantitative coronary angiography in post-MI patients [21].

References