Non-pathogenic E. coli can kill within 24 to 48 hr.
http://toxsci.oxfordjournals.org/cgi/content/full/87/1/75
Chemicals can suppress immunity and non-pathogenic E. coli can kill within 24 to 48 hr.
It remains to be determined whether death is caused by overgrowth of bacteria leading to intravascular
coagulation and multiple organ failure or whether there is a rebound in the production of pro-inflammatory
cytokines leading to systemic inflammatory response syndrome, shock, and death. A rebound effect
leading to increased concentrations of MIF, for example, after the effects of SMD subside, would be
expected to increase lethality due to systemic inflammatory response syndrome (Roger et al., 2001).
ToxSci Advance Access originally published online on June 2, 2005
Sodium Methyldithiocarbamate Inhibits MAP Kinase Activation through Toll-like Receptor 4, Alters
Cytokine Production by Mouse Peritoneal Macrophages, and Suppresses Innate Immunity
Stephen B. Pruett1, Qiang Zheng, Carlton Schwab and Ruping Fan
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport,
Louisiana 71130
Excerpts
Sodium methyldithiocarbamate (SMD; trade name, Metam Sodium) is an abundantly used soil fumigant that can cause
adverse health effects in humans, including some immunological manifestations. The mechanisms by which SMD acts,
and its targets within the immune system are not fully understood. Initial experiments demonstrated that SMD
administered by oral gavage substantially decreased IL-12 production and increased IL-10 production induced by
lipopolysaccharide in mice. The present study was conducted to further characterize these effects and to evaluate our
working hypothesis that the mechanism for these effects involves alteration in signaling through toll-like receptor 4 and
that this would suppress innate immunity to infection. SMD decreased the activation of MAP kinases and AP-1 but not
NF-B in peritoneal macrophages. The expression of mRNA for IL-1, IL-1ß, IL-18, IFN-, IL-12 p35, IL-12 p40, and
macrophage migration inhibitory factor (MIF) was inhibited by SMD, whereas mRNA for IL-10 was increased. SMD
increased the IL-10 concentration in the peritoneal cavity and serum and decreased the concentration of IL-12 p40 in
the serum, peritoneal cavity, and intracellularly in peritoneal cells (which are >80% macrophages). Similar effects on
LPS-induced cytokine production were observed following dermal administration of SMD. The major breakdown
product of SMD, methylisothiocyanate (MITC), caused similar effects on cytokine production at dosages as low as 17
mg/kg, a dosage relevant to human exposure levels associated with agricultural use of SMD. Treatment of mice with
SMD decreased survival following challenge with non-pathogenic Escherichia coli within 24–48 h, demonstrating
suppression of innate immunity.
The results presented here do not conclusively establish that the altered cytokine responses caused by SMD are
responsible for the decreased resistance to E. coli. It has been established that many of the genes regulated by E. coli
treatment of mice are similarly regulated by LPS (Huang et al., 2001; Nau et al., 2003). Considering that increased IL-
10 has been reported to decrease E. coli clearance (Takano et al., 1998) and that some of the cytokines suppressed
by SMD are involved in resistance to E. coli or similar bacteria (Cross et al., 1995; Kinoshita et al., 2004; Zisman et al.,
1997), it seems likely that these changes do contribute to decreased resistance. The mouse model used here is
relevant to a variety of conditions in humans (e.g., abdominal trauma, appendicitis, diverticulitis, chronic alcoholism) in
which large numbers of normally non-pathogenic bacteria enter the peritoneal cavity from the gastrointestinal tract
(Pruett et al., 2004b). It remains to be determined whether death is caused by overgrowth of bacteria leading to
intravascular coagulation and multiple organ failure or whether there is a rebound in the production of pro-
inflammatory cytokines leading to systemic inflammatory response syndrome, shock, and death. A rebound effect
leading to increased concentrations of MIF, for example, after the effects of SMD subside, would be expected to
increase lethality due to systemic inflammatory response syndrome (Roger et al., 2001).