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Published on: March 2, 2011
Interleukin-1 regulates cytokine gene expression in human mesangial cells through the interleukin-1 receptor type 1
1Mario Negri Institute for Pharmacological Research, Ospedali Riuniti di Bergamo, Italy.
Insights
Interleukin-1 (IL-1) stimulates its own gene expression in human mesangial cells, creating a positive feedback loop. This IL-1 loop may regulate cytokine secretion during kidney inflammation.
Area of Science:
- Immunology
- Cell Biology
- Nephrology
Background:
- Interleukin-1 (IL-1) is a key inflammatory mediator.
- Human mesangial cells play a role in glomerular inflammation.
- Previous studies showed IL-1 induces various factors in mesangial cells.
Purpose of the Study:
- To investigate if IL-1 induces its own gene expression in human mesangial cells.
- To examine the role of IL-1 receptor expression in mesangial cells.
- To understand the signaling pathways involved in IL-1 gene activation.
Main Methods:
- Northern blot analysis to quantify IL-1 mRNA levels.
- Exposure of human mesangial cells to varying concentrations of IL-1 beta.
- Treatment with IL-1 receptor antagonist and lipopolysaccharide.
Main Results:
- IL-1 induced IL-1 mRNA expression in a dose-dependent manner.
- Human mesangial cells constitutively express IL-1 receptor type 1, unaffected by IL-1 or other stimuli.
- IL-1 receptor antagonist blocked IL-1-induced mRNA accumulation.
- Lipopolysaccharide induced IL-1 mRNA via an IL-1-independent pathway.
Conclusions:
- IL-1 plays a central role in regulating mesangial cell cytokine genes.
- An IL-1-mediated positive feedback loop exists in mesangial cells.
- This feedback loop may control glomerular cytokine secretion during inflammation.
Abstract:
We have recently shown that interleukin-1 is a potent stimulus of gene expression and production of leukocyte chemotactic factors, colony-stimulating factors, and interleukin-6 in human mesangial cells in culture. Here, we sought to determine whether interleukin-1 induces its own gene expression in human mesangial cells. Interleukin-1 mRNA levels were quantitated by Northern blot analysis with total cellular RNAs isolated from human mesangial cells exposed for 6 h to medium alone or in the presence of human recombinant interleukin-1 beta (1 to 100 ng/mL). Interleukin-1 induced interleukin-1 mRNA expression in a dose-dependent manner. An additional finding of this study was that human mesangial cells constitutively express the 80 kd interleukin-1 receptor type 1 gene. When human mesangial cells were exposed to interleukin-1, interleukin-1 receptor expression was not modified. Similarly, other stimuli like tumor necrosis factor, transforming growth factor beta, or interleukin-6 did not modulate interleukin-1 receptor expression. Recombinant interleukin-1 receptor antagonist blocked the interleukin-1 mRNA as well as interleukin-6 and interleukin-8 mRNA accumulation induced by interleukin-1 beta. Lipopolysaccharide, which is a known stimulus for interleukin-1 transcription in several cell types, also induced interleukin-1 mRNA accumulation, thus indicating that lipopolysaccharide mediates interleukin-1 gene activation in human mesangial cells through an interleukin-1-independent pathway. These data support the pivotal role of interleukin-1 in regulating mesangial cell cytokine genes and may be taken to indicate the existence of an interleukin-1-mediated positive feedback loop that might control the secretion of active cytokines within the glomeruli when an immunological or inflammatory injury takes place.
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