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1 induces interlukin-8 and macrophage chemoattractant protein-1 through a connective tissue growth factor independent pathway
1 Department of Medicine, Kolling Institute, Sydney, NSW, Australia
2 Department of Medicine, Royal Prince Alfred Hospital, Sydney, NSW, Australia
3 Department of Medicine, St. Vincent's Hospital, Sydney, NSW, Australia
* To whom correspondence should be addressed. E-mail: carpol{at}med.usyd.edu.au.
Transforming growth factor-
1 (TGF-1) functions as an important immunomodulatory
cytokine in human kidney. Evidence suggests that connective tissue growth factor (CTGF) is an
important downstream mediator of the profibrotic effects of TGF-1. However, the role of
CTGF in TGF-1-induced chemokine production remains unknown. This study was undertaken
to determine whether CTGF is involved in mediating TGF-1 induced chemokine production in
renal proximal tubular (HK-2) cells. Interleukin-8 (IL-8) and macrophage chemoattractant
protein-1 (MCP-1) were measured. TGF-1 induced an increase in IL-8 and MCP-1 (both
P<0.05) compared to control levels. CTGF was effectively silenced using small interference
RNA (siRNA) in HK-2 cells. RT-PCR and real time PCR confirmed a 94% reduction in CTGF
mRNA. In the CTGF silenced cells, TGF-1-stimulated IL-8 and MCP-1 secretion was not
altered compared to control cells. Similarly basal secretion of IL-8 and MCP-1 was not changed
in CTGF silenced cells. The direct effect of CTGF (20, 200 and 400 ng/ml) on IL-8 and MCP-1
was assessed at 24, 48 and 72 hrs time points and no stimulation was observed. Our studies
further demonstrate that in the CTGF gene silenced cells CTGF partially mediates TGF-1-
induced fibronectin and collagen IV secretion. These data suggest that TGF-1-induced IL-8
and MCP-1 via CTGF independent pathway. TGF- mediates both fibrosis and chemokine
production in the proximal tubule of the kidney. However, CTGF plays a more specific role as a
downstream mediator of TGF-1-induced fibrosis.
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