Conjugated linoleic acid (CLA) is a dietary fatty acid that has received considerable attention due to its unique properties in rodent models including anti-cancer, anti-atherogenic and anti-diabetic effects. The effects of CLA are similar to those seen with ligands for peroxisome proliferator-activated receptor (PPARs), most notably of the PPARγ subtype. With the recent observation of a role for PPARγ in regulation of immune responses, we suspected that CLA could affect immune function, in particular macrophage activity. The goal of our study was to examine whether this dietary fatty acid has anti-inflammatory properties similar to those reported for PPARγ activators such as 15-deoxy prostaglandin J2 (PGJ2). In reporter assays, various CLA isomers activated PPARγ in RAW264.7 mouse macrophage (RAW) cells. CLA decreased the interferon-γ (IFNγ)-induced mRNA expression of mediators of inflammation including cyclooxygenase 2 (COX2), inducible NOS (iNOS), and tumor necrosis factor α (TNFα). Reporter assays also demonstrated reduced IFNγ-stimulated transcriptional activity of the iNOS and COX2 promoters by CLA. Consequently, CLA decreased the production of PGE2, TNFα and the inflammatory agent nitric oxide (NO) in RAW cells treated with IFNγ. Other pro-inflammatory cytokines such as IL-1β and IL-6 were similarly decreased by CLA treatment of RAW cells. In addition, various CLA isomers induced HL60 cell differentiation along the monocytic lineage as assessed by measuring expression of the cell surface marker CD14. This differentiation process, as well as the regulation of iNOS and COX2 by 15dPGJ2, is believed to involve PPARγ. Mutations of Leu468 and Glu471 to alanine in helix 12 of the ligand-binding domain of PPARγ resulted in a protein with strong dominant-negative activity (dnPPARγ). Transfecting dnPPARγ into RAW cells eliminated the ability of various CLA isomers to regulate the iNOS reporter construct. Taken together, these results suggest that CLA has anti-inflammatory properties that are mediated, at least in part, by the nuclear hormone receptor PPARγ.
|Number of pages
|Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
|Published - Apr 15 2002
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology