Abstract
We demonstrated that 4 mM butyrate induces apoptosis in murine peritoneal macrophages in a dose- and time-dependent manner as indicated by studies of cell viability, flow cytometric analysis of annexin-V binding, DNA ladder pattern and the determination of hypodiploid DNA content. The activity of caspase-3 was enhanced during macrophage apoptosis induced by butyrate and the caspase inhibitor z-VAD-FMK (100 microM) inhibited the butyrate effect, indicating the major role of the caspase cascade in the process. The levels of butyrate-induced apoptosis in macrophages were enhanced by co-treatment with 1 microg/ml bacterial lipopolysaccharide (LPS). However, our data indicate that apoptosis induced by butyrate and LPS involves different mechanisms. Thus, LPS-induced apoptosis was only observed when macrophages were primed with IFN-gamma and was partially dependent on iNOS, TNFR1 and IRF-1 functions as determined in experiments employing macrophages from various knockout mice. In contrast, butyrate-induced macrophage apoptosis was highly independent of IFN-gamma priming and of iNOS, TNFR1 and IRF-1 functions.
Highlights
Apoptosis is a process of programmed cell death which is essential in maintaining homeostasis of mammalian tissues
We show that the mechanism of induction of apoptosis seems to be dependent on caspases, especially caspase-3, but does not appear to involve the action of tumor necrosis factor α (TNF-α) or nitric oxide (NO)
To investigate the involvement of the autocrine production of TNF and NO in butyrate-induced apoptosis, we evaluated the responsiveness of macrophages derived from mice lacking genes for inducible NO synthase, type I receptor for TNF (TNFR1-/-), and interferon regulatory factor 1 (IRF-1-/-) with 4 mM butyrate or with LPS plus IFN-γ for 24 or 48 h
Summary
Apoptosis is a process of programmed cell death which is essential in maintaining homeostasis of mammalian tissues. Macrophages play an important role in initiating, maintaining and resolving host inflammatory responses. They are able to directly kill viruses, bacteria and parasites, to secrete several immune regulators, to process and present antigens, and to act as scavenger cells. Macrophages have deleterious effects on the host They can be dangerous in situations of excessive production of free radicals, lytic enzymes and inflammatory cytokines [3], which cause extensive local damage and are responsible for many of the systemic symptoms associated with acute and chronic inflammation. Macrophages can be deleterious to the organism when they become foam cells and contribute to the formation of atherosclerotic lesions. Apoptosis would seem a logical candidate to participate in macrophage regulation, as it is known to regulate other cells in the immune system such as activated T cells [6,7], B cells [8,9] and granulocytes [10]
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