Expression of the chemokines MCP-1/CCL2 and RANTES/CCL5 is differentially regulated by infiltrating inflammatory cells.
BACKGROUND
Chemokines are involved in the regulation of the cellular renal infiltrate in glomerulonephritis; however, it is unclear to which degree resident glomerular cells or infiltrating leukocytes contribute to the formation of chemokines in glomerular inflammatory lesions. We therefore examined whether monocytes/macrophages play a role in the expression of the C-C chemokines MCP-1/CCL2 and RANTES/CCL5 in renal tissue in a lipopolysaccharide (LPS)-induced model of inflammation, where previously we have shown increased glomerular RANTES expression and glomerular infiltration of ED-1-positive cells.


METHODS
Inflammatory lesions were induced by an intraperitoneal injection of LPS. The infiltration of monocytes into the glomerulus was reduced by two experimental approaches. First, rats were depleted of monocytes by the use of specific monocyte-antisera or by cytotoxic drugs. Second, the infiltration of monocytes into the kidney was reduced by using intercellular adhesion molecule-1 (ICAM-1) knockout mice.


RESULTS
Both experimental approaches demonstrated a significant reduction in the number of infiltrating monocytes/macrophages after lipopolysaccharide injection. This reduction in the infiltration of inflammatory cells was associated with significantly reduced RANTES/CCL5 mRNA expression. However, MCP-1/CCL2 mRNA expression was not inhibited after the LPS injection by monocyte/macrophage depletion. Also, the increase in nuclear factor-kappaB (NF-kappaB) binding activity after the LPS injection was not reduced in pretreated animals. The experiments therefore demonstrate that infiltrating monocytes/macrophages contribute to increased RANTES/CCL5 mRNA expression in inflammatory renal lesions, whereas MCP-1/CCL2 mRNA expression and NF-kappaB activation were not reduced by monocyte/macrophage depletion.


CONCLUSIONS
MCP-1/CCL2 released from renal tissue upon stimulation plays a major role in the regulation of monocyte/macrophage infiltration, which contributes significantly to increased renal RANTES/CCL5 expression. This cross-talk between resident renal cells and monocytes/macrophages is therefore likely to boost the number of infiltrating inflammatory cells.
Haberstroh
Uwe
U
Division of Nephrology and Osteology, Department of Internal Medicine, University Hospital, Hamburg 20246, Germany.
Pocock
Johanna
J
Gómez-Guerrero
Carmen
C
Helmchen
Udo
U
Hamann
Alf
A
Gutierrez-Ramos
Jose C
JC
Stahl
Rolf A K
RA
Thaiss
Friedrich
F
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics*; D018946:Chemokine CCL5 / Q000235:genetics*; D015870:Gene Expression / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology* / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007678:Kidney Glomerulus / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis
D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1