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Expression and regulation of human pulmonary fibroblast-derived monocyte chemotactic peptide-1
M W Rolfe1, S L Kunkel, T J Standiford
1Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0360.
Abstract:
Monocyte recruitment is essential for maintenance of normal pulmonary macrophage populations. In addition, acute and chronic inflammatory pulmonary diseases are associated with sequestration of mononuclear phagocytes in the lung. Although alveolar macrophages (AM phi) can secrete a number of potent inflammatory and chemoattractment mediators, these immune cells do not produce monocyte chemotactic peptide (MCP-1) in response to lipopolysaccharide (LPS), tumor necrosis factor (TNF), or interleukin-1 beta (IL-1 beta). The pulmonary fibroblast (PF) may play a pivotal role in monocyte recruitment. In these studies, we demonstrate a time- and dose-dependent production of PF-derived steady-state MCP-1 mRNA, MCP-1 antigen, and monocyte chemotactic bioactivity attributable to MCP-1. In cellular models examining cytokine networks between AM phi and PF, LSP-stimulated AM phi (conditioned media) induced PF-derived steady-state MCP-1 mRNA expression that was markedly attenuated by the presence of neutralizing TNF and IL-1 beta antibodies. Furthermore, we showed the dose- and time-dependent suppression of IL-1 beta-stimulated PF-derived MCP-1 by dexamethasone and prostaglandin E2. These findings demonstrated that PF are an important cellular source of MCP-1 and this production of MCP-1 may be influenced by immunomodulators.
Insights
Pulmonary fibroblasts produce monocyte chemotactic peptide-1 (MCP-1), a key molecule for recruiting monocytes to the lungs. This production is influenced by immune cells and can be modulated by anti-inflammatory drugs.
Area of Science:
- Immunology
- Pulmonary Medicine
- Cell Biology
Background:
- Monocyte recruitment is crucial for lung health and inflammatory disease.
- Alveolar macrophages (AM phi) do not produce monocyte chemotactic peptide-1 (MCP-1) when stimulated by common inflammatory signals.
- Pulmonary fibroblasts (PF) may be a significant source of MCP-1 in the lung.
Purpose of the Study:
- To investigate the role of pulmonary fibroblasts (PF) as a source of MCP-1.
- To explore the regulation of PF-derived MCP-1 production by immune cells and inflammatory mediators.
- To examine the impact of immunomodulators on PF-derived MCP-1 production.
Main Methods:
- Assessed time- and dose-dependent production of MCP-1 mRNA, antigen, and bioactivity in PF.
- Utilized cellular models to examine cytokine networks between AM phi and PF.
- Investigated the effects of lipopolysaccharide (LPS)-stimulated AM phi conditioned media on PF-derived MCP-1.
- Tested the influence of neutralizing antibodies against tumor necrosis factor (TNF) and interleukin-1 beta (IL-1 beta).
- Evaluated the dose- and time-dependent suppression of IL-1 beta-stimulated PF-derived MCP-1 by dexamethasone and prostaglandin E2.
Main Results:
- Pulmonary fibroblasts (PF) demonstrated time- and dose-dependent production of MCP-1 mRNA, antigen, and chemotactic bioactivity.
- LPS-stimulated AM phi conditioned media induced MCP-1 mRNA expression in PF, which was reduced by TNF and IL-1 beta neutralizing antibodies.
- Dexamethasone and prostaglandin E2 suppressed IL-1 beta-stimulated PF-derived MCP-1 in a dose- and time-dependent manner.
Conclusions:
- Pulmonary fibroblasts (PF) are a significant cellular source of MCP-1 in the lung.
- PF-derived MCP-1 production is influenced by inflammatory signals from alveolar macrophages (AM phi).
- The production of MCP-1 by PF can be modulated by immunomodulatory agents like dexamethasone and prostaglandin E2.