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Leukotrienes stimulate neutrophil adhesion to mesangial cells: modulation with lipoxins
H R Brady1, U Persson, B J Ballermann
1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Abstract:
We have examined polymorphonuclear neutrophil (PMN) adhesion to mesangial cells (MC) in vitro and have assessed the actions of lipoxygenase (LO) products in this process. On exposure to either leukotriene B4 (LTB4), or leukotriene D4 (LTD4), 111In-labeled PMNs adhere to monolayers of cultured MC. These actions were rapid in onset (less than 5 min) and dependent upon leukotriene concentration (10(-9) to 10(-6) M) and the presence of divalent cations. Adhesion was sustained (0-30 min), and neither LTB4 nor LTD4 was metabolized to inactive products during PMN-MC interaction, as determined by their recovery after reverse-phase high-performance liquid chromatography. LTB4 was a PMN-directed stimulus, whereas LTD4 appeared to act on MC. A monoclonal antibody (TS 1/18) against the CD18 component of the PMN CD18/CD11 adhesion complex inhibited the LTB4-induced response, indicating involvement of this PMN glycoprotein in the adhesion process. In contrast, this antibody did not affect LTD4-induced adhesion, suggesting that this response was mediated by other adhesion epitopes. When added alone, neither lipoxin A4 (LXA4) nor lipoxin B4 (LXB4) provoked PMN adhesion to MC. In contrast, LXA4 and LXB4 at equimolar concentrations attenuated the LTD4- but not LTB4-induced response. Together, these results provide further evidence that LO-derived eicosanoids may constitute important early signals that regulate PMN-MC interaction in glomerular inflammation.
Insights
Leukotrienes rapidly increase polymorphonuclear neutrophil (PMN) adhesion to mesangial cells (MC), with distinct pathways for LTB4 and LTD4. Lipoxins can modulate these inflammatory responses.
Area of Science:
- Immunology
- Cell Biology
- Inflammation Research
Background:
- Polymorphonuclear neutrophils (PMNs) play a role in glomerular inflammation.
- Mesangial cells (MCs) are key components of the glomerulus.
- Lipoxygenase (LO) products are implicated in inflammatory processes.
Purpose of the Study:
- To investigate the role of LO products in PMN adhesion to MCs in vitro.
- To differentiate the mechanisms of action for different leukotrienes (LTB4, LTD4) and lipoxins (LXA4, LXB4).
- To identify the adhesion molecules involved in PMN-MC interactions.
Main Methods:
- In vitro study using cultured human mesangial cells and 111In-labeled PMNs.
- Stimulation with leukotrienes (LTB4, LTD4) and lipoxins (LXA4, LXB4).
- Assessment of PMN adhesion using radioisotope labeling and quantification.
- Use of monoclonal antibody (TS 1/18) targeting CD18 adhesion complex.
- Reverse-phase high-performance liquid chromatography for metabolite analysis.
Main Results:
- LTB4 and LTD4 induced rapid and concentration-dependent PMN adhesion to MCs.
- LTB4-induced adhesion involved the CD18 adhesion complex, while LTD4-induced adhesion did not.
- LTB4 acted as a PMN-directed stimulus, whereas LTD4 appeared to act on MCs.
- LXA4 and LXB4 attenuated LTD4-induced adhesion but not LTB4-induced adhesion.
Conclusions:
- LO-derived eicosanoids, specifically LTB4 and LTD4, are important early regulators of PMN-MC interactions.
- Distinct molecular mechanisms mediate LTB4 and LTD4-induced PMN adhesion.
- Lipoxins can modulate inflammatory responses by inhibiting LTD4-induced PMN adhesion.