Altered NF-kappaB 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-kappaB) pathway. 3T3-Swiss fibroblasts were grown in medium containing either AA or EPA. Lipopolysaccharide (LPS) was used to activate NF-kappaB, and parthenolide was used to block it. Cells treated with EPA had increased expression of genes in the NF-kappaB pathway when exposed to LPS and also produced more collagen. Parthenolide blocked NF-kappaB activation to a greater extent in EPA-treated cells and also decreased CP induced by NF-kappaB activation. Genes in the NF-kappaB 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-kappaB-inducing kinase, inhibitors of kappa light polypeptide gene enhancer isoforms), inhibitor protein (I-kappaB alpha chain), transcription factors (nuclear factor of kappa light chain gene enhancer, (p)105 and NF-kappaB 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-kappaB pathway) to control collagen formation.
Jia
Yi
Y
Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907-2026, USA.
Turek
John J
JJ
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis*; D012717:Sesquiterpenes / Q000494:pharmacology; D041701:Swiss 3T3 Cells
D008070:Lipopolysaccharides; D016328:NF-kappa B; D012717:Sesquiterpenes; D016718:Arachidonic Acid; C002669:parthenolide; D003094:Collagen; D015118:Eicosapentaenoic Acid