Altered NF-κB gene expression and collagen formation induced by polyunsaturated fatty acids☆

Inability to control collagen formation in vital organs (e.g., fibrosis) or stimulate healthy collagen production (CP) in connective tissues (e.g., ligaments) is a major cause of death and disability. This study tested the hypothesis that arachidonic acid (AA) and eicosapentaenoic acid (EPA) influenced CP in 3T3-Swiss fibroblasts by altering gene expression in the nuclear factor-kappa B (NF-κB) pathway. 3T3-Swiss fibroblasts were grown in medium containing either AA or EPA. Lipopolysaccharide (LPS) was used to activate NF-κB, and parthenolide was used to block it. Cells treated with EPA had increased expression of genes in the NF-κB pathway when exposed to LPS and also produced more collagen. Parthenolide blocked NF-κB activation to a greater extent in EPA-treated cells and also decreased CP induced by NF-κB activation. Genes in the NF-κB signaling pathway that had increased expression in EPA-treated cells included the toll-like receptor 4 (Tlr4), adaptor proteins [TNF receptor-associated factor 6 (Traf6), myeloid differentiation primary response gene 88], signal transduction kinases (NF-κB-inducing kinase, inhibitors of kappa light polypeptide gene enhancer isoforms), inhibitor protein (I-κB alpha chain), transcription factors (nuclear factor of kappa light chain gene enhancer, p105 and NF-κB subunit p100), DNA binding proteins (cAMP response element binding protein) and response genes known to affect CP [interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), monocyte chemotactic protein-1]. This study raises the possibility that fatty acids may be used as adjuvants in combination with other therapies (e.g., selective targeting of the NF-κB pathway) to control collagen formation.