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.