Lymphocyte-derived cytokines induce sequential expression of monocyte- and T cell-specific chemokines in human
M Schwarz1, H H Radeke, K Resch
1Institute of Clinical Molecular Pharmacology, Medical School, Hannover, Germany.
Insights
Human glomerular mesangial cells produce chemokines like MCP-1 and RANTES. Cytokines such as TNF-alpha and IFN-gamma influence their expression kinetics, suggesting autocrine regulation in inflammation.
Area of Science:
- Immunology
- Cell Biology
- Nephrology
Background:
- Chemokines are crucial for leukocyte recruitment during inflammation.
- Glomerular mesangial cells are significant producers of various chemokines.
- Understanding mesangial cell chemokine regulation is key to inflammatory kidney diseases.
Purpose of the Study:
- To investigate the kinetics of mesangial cell chemokine expression.
- To determine the role of lymphocyte- and monocyte-derived cytokines in chemokine regulation.
- To explore the influence of mesangial cell growth factors on chemokine production.
Main Methods:
- Mesangial cells were stimulated with cytokines (IFN-gamma, TNF-alpha, IL-1 beta) and growth factors (bFGF).
- Chemokine mRNA and protein expression (MCP-1, RANTES, MIP-1 alpha, IL-8) were analyzed over time.
- Kinetic studies focused on the temporal patterns of gene and protein expression.
Main Results:
- IFN-gamma synergized with TNF-alpha for RANTES and with IL-1 beta for MCP-1 expression.
- TNF-alpha induced early MCP-1 mRNA peaking earlier than T cell-specific RANTES mRNA.
- MIP-1 alpha expression required TNF-alpha plus IFN-gamma, with kinetics similar to RANTES.
- Basic fibroblast growth factor induced MCP-1, RANTES, and IL-8, suggesting autocrine loops.
Conclusions:
- Mesangial cell chemokine expression is differentially regulated by specific cytokines.
- Distinct kinetic profiles for MCP-1 and RANTES suggest sequential roles in inflammation.
- Autocrine mechanisms involving growth factors may contribute to mesangial chemokine production.
Abstract:
Chemokines are a family of small related proteins that play an important role in the selective recruitment of different leukocyte populations to the sites of inflammation. Human glomerular mesangial cells are potent producers of a variety of chemokines. Here we examined the kinetics of mesangial cell chemokine expression with focus on the C-C or beta chemokines monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and the C-X-C or alpha chemokine interleukin-8 (IL-8) in response to lymphocyte- or monocyte-derived cytokines and mesangial cell growth factors. It was found that interferon-gamma (IFN-gamma), a cytokine produced by TH1 lymphocytes, synergized with tumor necrosis factor-alpha (TNF-alpha) in RANTES expression and with IL-1 beta in MCP-1 synthesis. Time course studies revealed an early peak of mRNA expression of monocyte-specific MCP-1 upon activation with TNF-alpha in contrast to T cell-specific RANTES, which reached the highest mRNA level after 18 hours. This sequence of TNF-alpha-induced MCP-1 and RANTES expression was confirmed on the protein level. As another T-lymphocyte specific chemokine, MIP-1 alpha mRNA and protein was expressed only in response to TNF-alpha plus IFN-gamma with kinetics similar to those of RANTES expression. Finally, unlike other mesangial growth factors basic fibroblast growth factor (bFGF) induced MCP-1, RANTES, and IL-8 mRNA expression, suggesting an involvement of autocrine regulation mechanisms in mesangial chemokine expression.
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