Global gene expression changes underlying Stachybotrys chartarum toxin-induced apoptosis in murine alveolar macrophages: Evidence of multiple signal transduction pathways

Abstract

The overall mechanism(s) underlying macrophage apoptosis caused by the toxins of the indoor mold Stachybotrys chartarum (SC) are not yet understood. In this direction, we report a microarray-based global gene expression profiling on the murine alveolar macrophage cell line (MH-S) treated with SC toxins for short (2 h) and long (24 h) periods, coinciding with the pre-apoptotic (<3 h) and progressed apoptotic stages of the treated cells, respectively. Microarray results on differential expression were validated by real-time RT-PCR analysis using representative gene targets. The toxin-regulated genes corresponded to multiple cellular processes, including cell growth, proliferation and death, inflammatory/immune response, genotoxic stress and oxidative stress, and to the underlying multiple signal transduction pathways involving MAPK-, NF-kB-, TNF-, and p53-mediated signaling. Transcription factor NF-kB showed dynamic temporal changes, characterized by an initial activation and a subsequent inhibition. Up-regulation of a battery of DNA damage-responsive and DNA repair genes in the early stage of the treatment suggested a possible role of genotoxic stress in the initiation of apoptosis. Simultaneous expression changes in both pro-survival genes and pro-apoptotic genes indicated the role of a critical balance between the two processes in SC toxin-induced apoptosis. Taken together, the results imply that multiple signaling pathways underlie the SC toxin-induced apoptosis in alveolar macrophages.

Procaspase 8 and Bax Are Up-regulated by Distinct Pathways in Streptococcal Pyrogenic Exotoxin B-induced Apoptosis

“…p53 has a positive role in Bax gene expression, and p38 MAPK is required for the activation of p53 in UV-induced apoptosis (32,33). The p53-mediated signaling events have been reported in several accounts of toxin-induced apoptosis, which involves the p38-dependent activation of p53 (34,35). Our preliminary results also show that SPE B can trigger the Fas-mediated p38/p53 signal pathway (data not shown).…”

“…Interferon-␥ acts on human erythroid progenitor cells to induce the expression of Fas and caspases 1, 3, and 8, which promote cell death (37). Stachybotrys chartarum toxin induced apoptosis in murine alveolar macrophages involved the gene expression of caspase-related genes (35). Although some other streptococcal virulence factors have been reported to be involved in apoptosis, their mode of action is less clear (38,39).…”

Prenatal and postnatal risk factors for infantile pneumonia in a representative birth cohort

“…Fusariumproduced T2 toxin was able to induce apoptotic death of alveolar macrophages, decrease secretory IgA titres, and potentiate reovirus-induced inflammation and tissue injury in mice [30]. Stachybotrys chartarum toxins induced apoptosis in pulmonary alveolar macrophages, reduced alveolar type II cell function and anti-oxidative ability, and interfered with surfactant homeostasis [31][32][33][34]. Additionally, several indoor mould-related mycotoxins were able to inhibit airway ciliary function in chickens [35].…”

Mechanisms of Mycotoxin-Induced Neurotoxicity through Oxidative Stress-Associated Pathways

“…The methanol extract of a trichothecene-producing strain of S. chartarum particularly up-regulates DNA damage-responsive and DNA repair genes in the murine alveolar macrophage cell line MH-S early in the treatment, which are suggestive of genotoxic stress [81]. In a follow-up study, extract-induced apoptosis in MH-S cells was observed to precede DNA damage [82].…”