Interleukin-8 production by THP-1 cells stimulated by Salmonella enterica serovar Typhimurium porins is mediated by AP-1, NF-kappaB and MAPK pathways.
Interleukin-8 (IL-8) is released in response to inflammatory stimuli, such as bacterial products. Either porins or lipopolysaccharide (LPS) stimulated THP-1 cells to release IL-8 after 24 h. We have previously reported that stimulation of monocytic cells with Salmonella enterica serovar Typhimurium porins led to the activation of mitogen-activated protein kinase cascades and of protein tyrosine kinases (PTKs). In this report, we demonstrate, using two potent and selective inhibitors of MEK activation by Raf-1 (PD-098059) and p38 (SB-203580), that both ERK1/2 and p38 pathways play a key role in the production of IL-8 by porins and LPS. Porin-stimulated expression of activating protein 1 (AP-1) and correlated IL-8 release is also inhibited by PD-098059 or SB-203580 indicating that the Raf-1/MEK1-MEK2/MAPK cascade is required for their activation. Also PTKs modulate the pathway that control IL-8 gene expression, in fact its expression is abolished by tyrphostin. By using N-acetyl-leucinyl-leucinyl-norleucinal-H (ALLN) an inhibitor of nuclear factor-kappaB (NF-kappaB) activity, we also observed IL-8 release modulation. Our results elucidate some of the molecular mechanisms by which AP-1 and NF-kappaB regulate IL-8 release and open new strategies for the design of specific molecules that will modulate IL-8 effects in various infectious diseases.
Vitiello
M
M
Dipartimento di Patologia Generale, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli, 80138 Naples, Italy.
D'Isanto
M
M
Galdiero
M
M
Raieta
K
K
Tortora
A
A
Rotondo
P
P
Peluso
L
L
Galdiero
M
M
D002460:Cell Line; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018272:Porins / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
D005419:Flavonoids; D007093:Imidazoles; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018272:Porins; D011725:Pyridines; D018808:Transcription Factor AP-1; D020032:Tyrphostins; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one