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Interleukins and interferons: yin-yang modulators of PGH synthase in human macrophages
G Bartolini1, M Orlandi, M Chiricolo
1Department of Experimental Biology, University of Bologna, Italy.
Abstract:
Prostaglandin H synthase (PGHs) not only is an unstable enzyme, mainly when it is challenged with substrate, but its mRNA is one of the shortest lived species so far identified in mammalian cells. Therefore, signals regulating its level are critical for the role it plays in many cells. The expression of genes coding for PGHs appears to be under the control of polypeptide growth factors. This is in accordance with our previous data showing that a colony stimulating factor-1 (CSF-1)-like factor induces the de novo synthesis of PGHs in human monocytes, as demonstrated by immunoblotting. Here we extend this concept by showing that interleukin (IL)-1 alpha behaves as a potent inducer of PGHs in human macrophages, as indicated by the block in its action due to the addition of RNA and protein synthesis inhibitors. Interferons (IFNs) alpha and beta, however, inhibit prostanoid production in a dose-dependent fashion mainly when macrophages activated by serum are tested. Thus, the PGHs system appears to be under a fine control, CSF-1 being the main regulator during the differentiation from pro-monocyte to monocyte and from monocyte to macrophage, and IL-1 (and perhaps IL-2) as well as IFN alpha and beta, the regulators during differentiation and/or proliferation of human macrophages.
Insights
Colony stimulating factor-1 (CSF-1) regulates prostaglandin H synthase (PGHs) during monocyte differentiation. Interleukin-1 alpha and interferons also modulate PGHs in macrophages, indicating fine control of this enzyme system.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Prostaglandin H synthase (PGHs) is an unstable enzyme with rapidly degraded mRNA.
- PGHs plays a critical role in various cellular functions.
- Gene expression of PGHs is influenced by polypeptide growth factors.
Purpose of the Study:
- To investigate the regulatory mechanisms of PGHs expression in human monocytes and macrophages.
- To identify specific signaling molecules that control PGHs levels.
- To elucidate the role of growth factors and cytokines in PGHs regulation.
Main Methods:
- Immunoblotting to detect PGHs protein levels.
- Use of RNA and protein synthesis inhibitors to assess induction.
- Dose-dependent experiments with interferons.
Main Results:
- Colony stimulating factor-1 (CSF-1) induces de novo synthesis of PGHs in human monocytes.
- Interleukin-1 alpha (IL-1 alpha) potently induces PGHs in human macrophages.
- Interferons (IFNs) alpha and beta inhibit prostanoid production in activated macrophages.
Conclusions:
- CSF-1 is a key regulator of PGHs during monocyte differentiation.
- IL-1 alpha and potentially IL-2, along with IFN alpha and beta, regulate PGHs in macrophages.
- The PGHs system is finely tuned by various signaling molecules during immune cell development and function.