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Mesangial cell-derived interleukin-10 modulates mesangial cell response to lipopolysaccharide
B Fouqueray1, V Boutard, C Philippe
1INSERM,* Tenon Hospital, Paris, France.
Insights
Interleukin-10 (IL-10) is produced by mesangial cells when exposed to lipopolysaccharide (LPS). This cytokine helps regulate the inflammatory response to LPS by reducing tumor necrosis factor-alpha generation.
Area of Science:
- Immunology
- Cell Biology
- Renal Physiology
Background:
- Interleukin-10 (IL-10) is a cytokine with known immunomodulatory functions.
- Lipopolysaccharide (LPS) is a potent activator of inflammatory responses in various cell types, including mesangial cells.
- The role of IL-10 in mesangial cell response to LPS was not fully understood.
Purpose of the Study:
- To investigate the synthesis and function of IL-10 in cultured mouse mesangial cells.
- To determine if IL-10 regulates the production of inflammatory mediators by LPS-stimulated mesangial cells.
- To explore factors influencing IL-10 production in these cells.
Main Methods:
- Cultured mouse mesangial cells were treated with LPS.
- IL-10 mRNA expression was analyzed using reverse transcription polymerase chain reaction (RT-PCR).
- IL-10 protein secretion was measured by enzyme-linked immunosorbent assay (ELISA).
- The effects of recombinant IL-10 and anti-IL-10 antibodies on inflammatory mediator production (TNF-alpha, IL-1 beta, nitrite/nitrate) were assessed.
Main Results:
- LPS induced dose- and time-dependent expression and secretion of IL-10 by mesangial cells.
- Recombinant IL-10 significantly inhibited LPS-induced TNF-alpha and IL-1 beta production.
- Endogenous IL-10, modulated by anti-IL-10 antibodies, primarily affected TNF-alpha generation.
- Desferrioxamine and transforming growth factor-beta increased IL-10 release from mesangial cells.
Conclusions:
- Mesangial cells synthesize and release IL-10 in response to LPS.
- Mesangial cell-derived IL-10 plays a crucial role in modulating the inflammatory response to LPS, specifically by suppressing TNF-alpha.
- IL-10 represents an important autocrine/paracrine regulator of inflammation in mesangial cells.
Abstract:
Interleukin (IL)-10 is a novel cytokine produced by a variety of cells, including monocytes/macrophages, upon exposure to lipopolysaccharide (LPS). Recent observations indicate that, in turn, IL-10 exerts suppressive effects on macrophage response to LPS. Because mesangial cells are also a target for LPS, we have examined the potential role of IL-10 in the regulation of mesangial cell response to LPS. To this aim, we have studied the synthesis and the autocrine/paracrine function of IL-10 in cultured mouse mesangial cells. IL-10 mRNA expression and IL-10 protein secretion were determined by a reverse transcription polymerase chain reaction technique and a specific enzyme-linked immunosorbent assay, respectively. No IL-10 mRNA expression was detectable in unactivated cells. LPS induced IL-10 mRNA expression in a dose-dependent fashion (1 to 100 micrograms/ml). In addition, LPS induced IL-10 protein release that was both dose dependent (1 to 100 micrograms/ml) and time dependent (24 to 72 hours). We have also studied the effect of IL-10 on the production of inflammatory mediators by LPS-activated mouse mesangial cells. Whereas recombinant IL-10 inhibited the generation of tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta by 90 and 60%, respectively, it did not affect the formation of nitric oxide-derived nitrite (NO2-) and nitrate (NO3-). As shown by the use of anti-IL-10 monoclonal antibody, endogenously produced IL-10 affected the generation of TNF-alpha but neither that of IL-1 beta nor that of NO2- and NO3-. Finally, we have examined whether conditions known to also reduce the generation of TNF-alpha modified the expression of IL-10. Of all the conditions tested, only the addition of desferrioxamine and transforming growth factor-beta were found to increase IL-10 release. Together, these data demonstrate that mesangial cell-derived IL-10 has important regulatory effects on the inflammatory response of these cells to LPS because of its capacity to blunt TNF-alpha generation.
