Comment: Cytokines and chemokines are elevated in chronic fatigue syndrome (CFS) and were recently proposed as a biomarker to diagnose CFS.
Terameprocol, a methylated derivative of nordihydroguaiaretic acid, inhibits production of prostaglandins and several key inflammatory cytokines and chemokines
http://www.journal-inflammation.com/content/pdf/1476-9255-6-2.pdf
Eads D, Hansen R, Oyegunwa B, Cecil C, Culver C, Scholle F, Petty I, Laster S
Journal of Inflammation, 2009 6:2 ( 8 January 2009 )
Abstract
Background: Extracts of the creosote bush, Larrea tridentata, have been used for
centuries by natives of western American and Mexican deserts to treat a variety of
infectious diseases and inflammatory disorders. The beneficial activity of this plant has
been linked to the compound nordihydroguaiaretic acid (NDGA) and its various
substituted derivatives. Recently, tetra-O-methyl NDGA or terameprocol (TMP) has
been shown to inhibit the growth of certain tumor-derived cell lines and is now in clinical
trials for the treatment of human cancer. In this report, we ask whether TMP also
displays anti-inflammatory activity. TMP was tested for its ability to inhibit the LPSinduced
production of inflammatory lipids and cytokines in vitro. We also examined the
effects of TMP on production of TNF-α in C57BL6/J mice following a sublethal
challenge with LPS. Finally, we examined the molecular mechanisms underlying the
effects we observed.
Methods: RAW 264.7 cells and resident peritoneal macrophages from C57BL6/J mice,
stimulated with 1μg/ml LPS, were used in experiments designed to measure the effects
of TMP on the production of prostaglandins, cytokines and chemokines. Prostaglandin
production was determined by ELISA. Cytokine and chemokine production were
determined by antibody array and ELISA.
Western blots, q-RT-PCR, and enzyme assays were used to assess the effects of TMP
on expression and activity of COX-2.
q-RT-PCR was used to assess the effects of TMP on levels of cytokine and chemokine
mRNA.
C57BL6/J mice injected i.p. with LPS were used in experiments designed to measure
the effects of TMP in vivo. Serum levels of TNF-α were determined by ELISA.
Results: TMP strongly inhibited the production of prostaglandins from RAW 264.7 cells
and normal peritoneal macrophages. This effect correlated with a TMP-dependent
reduction in levels of COX-2 mRNA and protein, and inhibition of the enzymatic activity
of COX-2.
TMP inhibited, to varying degrees, the production of several cytokines, and chemokines
from RAW 264.7 macrophages and normal peritoneal macrophages. Affected
molecules included TNF-α and MCP-1. Levels of cytokine mRNA were affected
similarly, suggesting that TMP is acting to prevent gene expression.
TMP partially blocked the production of TNF-α and MCP-1 in vivo in the serum of
C57BL6/J mice that were challenged i.p. with LPS.
Conclusions: TMP inhibited the LPS-induced production of lipid mediators and several
key inflammatory cytokines and chemokines, both in vitro and in vivo, raising the
possibility that TMP might be useful as a treatment for a variety of inflammatory
disorders.
