From: Kofi on
As I pointed out several years ago, the mu opioid/cannabinoid complex is
under epigenetic control (via OCTN2/butyrate/carnitine uptake) and there
was evidence even back then that cannabinoid signals limited lymphocyte
proliferation. Now we have more direct evidence of this via PPARalpha,
a regulator of OCTN2.

Mol Immunol. 2009 Oct;46(16):3454-61. Epub 2009 Sep 11

PPARalpha ligands cause lymphocyte depletion and cell cycle block and
this is associated with augmented TRB3 and reduced Cyclin B1 expression.
Morse E, Selim E, Cunard R.
Research Service and Division of Nephrology-Hypertension, Veterans
Affairs San Diego Healthcare System, Veterans Medical Research
Foundation, San Diego, CA 92161, USA.

PPARalpha ligands are medications used clinically to prevent
cardiovascular events, however studies have shown that these agents are
also anti-inflammatory. Our previous studies have shown that PPARalpha
ligands induce lymphocyte depletion. PPARalpha ligands also potently
upregulate TRB3, a protein that has been associated with cell cycle
arrest. Therefore the following studies were undertaken to determine the
mechanisms associated with lymphocyte depletion. Our studies demonstrate
that WY14,643, a PPARalpha ligand, decreases the amount of lymphocytes
recovered after stimulation and reduces cellular divisions. Cells
treated with WY14,643 also accumulate in the G2/S phase of the cell
cycle. TRB3 has been shown to inhibit the phosphorylation of AKT/Protein
Kinase B, and reduced activation of AKT has been associated with
decreased cellular divisions and survival. However in lymphocytes, TRB3
did not reduce the phosphorylation of AKT, and WY14,643 treatment was
associated with enhanced activation of AKT. Drosophila tribbles (TRB3
homolog) causes G2 arrest by decreasing the expression of a Cdc25c
homolog. Lymphocytes stimulated and treated with WY14,643 have reduced
expression of Cdc25c, however this is not associated with enhanced
expression of phosphorylated-Cdc2 which induces G2 arrest. Instead we
observed that WY14,643 consistently reduces the protein and mRNA
expression of Cyclin B1. Moreover, TRB3 inhibits activation of a Cyclin
B1 promoter construct. In summary, we propose that PPARalpha ligands may
reduce cellular number by augmenting TRB3 expression, which in turn
induces cell cycle arrest by reducing the expression of Cyclin B1.
Reduced cellular divisions and cell cycle arrest may be responsible for
some of the immunomodulatory effects of these agents that have been
consistently observed in human trials.

Publication Types:
* Research Support, Non-U.S. Gov't
* Research Support, U.S. Gov't, Non-P.H.S.

PMID: 19748123