Induction of Suppressors of Cytokine Signaling by the Trichothecene Deoxynivalenol in the Mouse

Abstract

Deoxynivalenol (DON), a trichothecene mycotoxin found in grains and cereal-based foods worldwide, impairs weight gain in experimental animals but the underlying mechanisms remain undetermined. Oral exposure to DON induces rapid and transient upregulation of proinflammatory cytokine expression in the mouse. The latter are known to induce several suppressors of cytokine signaling (SOCS), some of which impair growth hormone (GH) signaling. We hypothesized that oral exposure to DON will induce SOCS expression in the mouse. Real-time PCR and cytokine bead array revealed that oral gavage with DON rapidly (1 h) induced tumor necrosis factor-alpha and interleukin-6 mRNA and protein expression in several organs and plasma, respectively. Upregulation of mRNAs for four well-characterized SOCS (CIS [cytokine-inducible SH2 domain protein], SOCS1, SOCS2, and SOCS3) was either concurrent with (1 h) or subsequent to cytokine upregulation (2 h). Notably, DON-induced SOCS3 mRNAs in muscle, spleen and liver, with CIS1, SOCS1, and SOCS2 occurring to a lesser extent. Hepatic SOCS3 mRNA was a very sensitive indicator of DON exposure with SOCS3 protein being detectable in the liver well after the onset of cytokine decline (5 h). Furthermore, hepatic SOCS upregulation was associated with about 75% suppression of GH-inducible insulin-like growth factor acid labile subunit. Taken together, DON-induced cytokine upregulation corresponded to increased expression of several SOCS, and was associated with suppression of GH-inducible gene expression in the liver.

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

“…Thus, in terms of wound healing, ribosomal insult-induced SOCS3 could retard the regeneration or restitution process after ribosomal stress-induced mucosal injuries. Moreover, the growth-inhibitory action via SOCS is consistent with the findings of recent studies on the suppression of growth-related signals (69,70). According to these reports, DON (a chemical ribosomal stress agent) induced SOCS proteins after the onset of proinflammatory cytokine decline, and this induction was involved in impaired growth hormone signaling in liver.…”

An analysis of the phosphoproteome of immune cell lines exposed to the immunomodulatory mycotoxin deoxynivalenol

“…Studies in animal models and immortalized cell lines have also shown that DON exposure modulates immune function by specifically influencing proinflammatory responses and white blood cell distribution and proliferation in several organs [7][8][9][10].…”

“…The primary mode of action of DON is thought to be its ability to bind to eukaryotic ribosomes and thereby inhibit protein synthesis [8,11]. Secondary mechanisms such as disruption of cell signaling, differentiation, growth and macromolecular synthesis have also been associated with DON exposure [8,11].…”

Role of tumor necrosis factor-α and interleukin-1β in anorexia induction following oral exposure to the trichothecene deoxynivalenol (vomitoxin) in the mouse

“…Anorexia induced by DON is of particular concern from the perspective of human and animal health (Forsell et al, 1986;Iverson et al, 1995;JECFA, 2011). However, the mechanistic basis for this adverse effect remains not fully understood but likely results from upregulation of proinflammatory cytokines and neuroendocrine hormones that influence food intake and appetite (Amuzie et al, 2009;Flannery et al, 2011;Girardet et al, 2011a;Wu et al, 2014a).…”

“…DON can stimulate TNF-α and IL-1β mRNA expression and protein secretion in human monocyte cell lines, human peripheral blood monocytes and mouse macrophage cell lines (Wong et al, 1998;SugitaKonishi and Pestka, 2001;Chung et al, 2003;He et al, 2013). Exposure of animals to DON also evokes robust production of TNF-α and IL-1β in plasma (Zhou et al, 1999;Islam and Pestka, 2006) and many organs including the spleen, liver, kidney, lung and brain (Amuzie et al, , 2009Girardet et al, 2011b). Increased cytokine gene transcription and enhanced mRNA stability contribute to DON-induced upregulation of proinflammatory cytokine mRNAs and ultimately, proteins (Pestka, 2010b).…”