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Methionine sulfoximine reduces proinflammatory cytokine release by murine macrophages
Author(s) -
Peters Tyler,
Jambekar Amruta,
Brusilow William
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.615.4
Subject(s) - cytokine , proinflammatory cytokine , secretion , glutamine synthetase , glutamine , tumor necrosis factor alpha , chemistry , immune system , biology , biochemistry , microbiology and biotechnology , pharmacology , inflammation , immunology , amino acid
Methionine sulfoximine (MSO) is an amino acid that irreversibly inhibits glutamine synthetase (GS). Several studies have linked aberrant GS activity with pathological states, and GS inhibition by MSO has been extensively reviewed. We have previously shown that IP injection of MSO (50mg/kg) increases survival and decreases pro‐inflammatory cytokine levels in a mouse model of acute liver failure. We are trying to characterize this activity, and we present evidence that MSO directly modulates the innate immune response by decreasing cytokine secretion by macrophages. Primary rat kupffer cells and mouse peritoneal macrophages were treated with MSO prior to addition of 1ug/mL LPS. A cytokine array analysis demonstrated appreciable decreases of TNFα and IL‐6 in the supernatants from cells treated with MSO compared to controls. These data were confirmed by ELISA quantification showing that MSO significantly reduced the levels of TNFα and IL‐6 at both 4 hours and 6 hours after LPS treatment in both cell culture models (p<0.05). We are currently attempting to establish a link between GS inhibition and cytokine secretion, but because these studies used a racemic mixture of LS and LR MSO, we have also treated macrophages with the purified LR isomer, which does not inhibit GS. Preliminary results show that the LR isomer does affect the cytokine response, suggesting an additional target for MSO besides glutamine synthetase.