Interleukin-1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase-1 production via activation of MAPK/AP-1 and NF-κB in human gingival fibroblasts

Abstract Interleukin-1 (IL-1) plays a crucial role in the immunopathological responses involved with tissue destruction in chronic inflammatory diseases, such as periodontal disease, as it stimulates host cells including fibroblasts to produce various inflammatory mediators and catabolic factors. We comprehensively investigated the involvement of mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) and IκB kinases (IKKs)/IκBs/nuclear factor-κB (NF-κB) in IL-1β-stimulated IL-6, IL-8, prostaglandin E 2 (PGE 2 ) and matrix metalloproteinase-1 (MMP-1) production by human gingival fibroblasts (HGF). Three MAPKs, extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK), which were simultaneously activated by IL-1β, mediated subsequent c-fos and c-jun mRNA expression and DNA binding of AP-1 at different magnitudes. IKKα/β/IκB-α/NF-κB was also involved in the IL-1 signaling cascade. Further, IL-1β stimulated HGF to produce IL-6, IL-8, PGE 2 and MMP-1 via activation of the 3 MAPKs and NF-κB, as inhibitors of each MAPK and NF-κB significantly suppressed the production of IL-1β-stimulated factors, though these pathways might also play distinct roles in IL-1β activities. Our results strongly suggest that the MAPKs/AP-1 and IKK/IκB/NF-κB cascades cooperatively mediate the IL-1β-stimulated synthesis of IL-6, IL-8, PGE 2 and MMP-1 in HGF.