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Monokines and platelet-derived growth factor modulate prostanoid production in growth arrested, human mesangial cells
1Department of Nephrology, Medizinische Hochschule Hannover, Federal Republic of Germany.
Abstract:
Previous studies have demonstrated considerable prostanoid production by cultured proliferating rat mesangial cells (MC). In this study, human mesangial cells (HMC) were examined during serum-free culture in which the cells were reversibly growth arrested and did not suffer obvious irreversible functional changes. Non-stimulated cells released 2 to 10 pg/24 hr/micrograms cellular protein of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, while TXB2 was not detectable. Stimulation with interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) induced up to 18-fold (IL-1 beta) or up to fourfold (TNF alpha) increases of prostanoid release. Combinations of the two monokines resulted in significant synergistic induction of PGE2 and 6-keto-PGF1 alpha up to 38 times that of control cells. Interleukin-6 (IL-6) and the HMC-mitogen, platelet-derived growth factor-BB (PDGF-BB) only induced marginal increases in HMC prostanoid generation. However, when PDGF-BB or -AB was combined with IL-1 beta or IL-6, prostanoid generation by HMC was synergistically increased up to 222-fold (IL-1 beta) or 12-fold (IL-6) above the control values, with the induction of PGE2 greater than 6-keto-PGF1 alpha greater than PGF2 alpha much greater than TXB2. In the case of IL-1 beta + PDGF-BB the induction of PGE2 release was at least partly due to the synergistic induction of cyclooxygenase activity. These findings demonstrate that both proliferating and reversibly growth arrested HMCs release prostaglandins in response to various inflammatory stimulators and combinations thereof. The findings support the important role of HMC in the regulation of glomerular hemodynamics during inflammatory processes.
Insights
Human mesangial cells (HMC) release prostaglandins, key inflammatory mediators, when stimulated by cytokines like IL-1 beta and TNF alpha. Combinations of these signals significantly amplify prostanoid production, impacting kidney function.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Previous research indicated prostanoid production by rat mesangial cells.
- Human mesangial cells (HMC) are crucial for kidney function and inflammatory responses.
Purpose of the Study:
- To investigate prostanoid production by human mesangial cells (HMC) under varying conditions, including stimulation with inflammatory cytokines.
- To determine the synergistic effects of combined stimuli on HMC prostanoid release.
Main Methods:
- Cultured human mesangial cells (HMC) in serum-free conditions, inducing reversible growth arrest.
- Stimulated HMC with interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), and platelet-derived growth factor-BB (PDGF-BB), individually and in combination.
- Measured prostanoid (PGE2, PGF2 alpha, 6-keto-PGF1 alpha, TXB2) release using established assays.
Main Results:
- Non-stimulated HMC produced basal levels of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha.
- IL-1 beta and TNF alpha significantly increased prostanoid release, with IL-1 beta showing a more potent effect.
- Combinations of IL-1 beta or IL-6 with PDGF-BB resulted in synergistic prostanoid induction, particularly PGE2.
- Synergistic induction of cyclooxygenase activity was observed with IL-1 beta and PDGF-BB.
Conclusions:
- Both proliferating and growth-arrested HMC release prostaglandins in response to inflammatory stimuli.
- Combined inflammatory signals can synergistically enhance prostanoid production by HMC.
- HMC play a significant role in regulating glomerular hemodynamics during inflammation.