Abstract
In this study, we analyzed the regulation and functional role of CXCL16 in human mesangial cells (hMCs). We can show, that CXCL16 is constitutively expressed in hMCs and is further up-regulated by cytokine mix (IFNgamma, TNFalpha, and IL1beta). The constitutive release of CXCL16 from hMCs was rapidly induced by the stimulation with cytokines. We identified ADAM10 and ADAM17 as being responsible for the cytokine-induced shedding of CXCL16. Notably, targeting ADAM10 and ADAM17 in hMCs decreased the chemotaxis of T-Jurkat cells, whereas the inhibition of CXCL16 had no significant influence. This suggests that both proteases are important players in the recruitment of immune cells into the glomerulus, but other substrates than CXCL16 are involved in this process. Finally, we could show that the inhibition of CXCL16, ADAM10, and ADAM17 led to a strong reduction of cell proliferation and migration of hMCs. This finding could be important to develop novel diagnostic and therapeutic strategies to treat mesangial proliferative kidney diseases.
MeSH terms
-
ADAM Proteins / antagonists & inhibitors
-
ADAM Proteins / genetics
-
ADAM Proteins / metabolism*
-
ADAM10 Protein
-
ADAM17 Protein
-
Amyloid Precursor Protein Secretases / antagonists & inhibitors
-
Amyloid Precursor Protein Secretases / genetics
-
Amyloid Precursor Protein Secretases / metabolism*
-
Cell Movement / drug effects
-
Cell Proliferation / drug effects
-
Cells, Cultured
-
Chemokine CXCL16
-
Chemokines, CXC / antagonists & inhibitors
-
Chemokines, CXC / genetics
-
Chemokines, CXC / metabolism*
-
Chemotaxis / drug effects
-
Cytokines / metabolism*
-
Cytokines / pharmacology
-
Humans
-
Inflammation / immunology
-
Inflammation / metabolism
-
Jurkat Cells
-
Membrane Proteins / antagonists & inhibitors
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Mesangial Cells / drug effects
-
Mesangial Cells / metabolism
-
Mesangial Cells / physiology*
-
RNA, Small Interfering / genetics
-
RNA, Small Interfering / pharmacology
-
Receptors, Scavenger / antagonists & inhibitors
-
Receptors, Scavenger / genetics
-
Receptors, Scavenger / metabolism*
-
T-Lymphocytes / drug effects
-
T-Lymphocytes / immunology
Substances
-
CXCL16 protein, human
-
Chemokine CXCL16
-
Chemokines, CXC
-
Cytokines
-
Membrane Proteins
-
RNA, Small Interfering
-
Receptors, Scavenger
-
Amyloid Precursor Protein Secretases
-
ADAM Proteins
-
ADAM10 Protein
-
ADAM10 protein, human
-
ADAM17 Protein
-
ADAM17 protein, human