Propionibacterium acnes-induced iNOS and COX-2 protein expression via ROS-dependent NF-?B and AP-1 activation in macrophages.

Propionibacterium acnes-induced iNOS and COX-2 protein expression via ROS-dependent NF-?B and AP-1 activation in macrophages.

J Dermatol Sci. 2012 Oct 24;

Authors: Tsai HH, Lee WR, Wang PH, Cheng KT, Chen YC, Shen SC

Abstract
BACKGROUND: Propionibacterium acnes (P. acnes), a gram-positive anaerobic bacterium, plays a critical role in the development of inflammatory lesion as a result of cytokines production by keratinocytes and macrophages activation. However, effect of P. acnes on iNOS/NO and COX-2/PGE(2) production in macrophages is still uninvestigated. OBJECTIVE: This study aimed at determining the reactive oxygen species (ROS), inducible nitric oxide (NO) synthase (iNOS)/nitric oxide (NO), and cyclooxygenase (COX)-2/prostaglandin (PG)E(2) produced by macrophages upon P. acnes infection, and dissecting the mechanism of P. acnes-stimulated multiplicity of infection (MOI)-dependent increases in iNOS and COX-2 protein expressions in accordance with the elevation of NO and PGE(2) production by RAW264.7 macrophages. METHODS: Using an in vitro cell culture system, the effects of P. acnes on iNOS/NO, COX-2/PGE(2), ROS production, ERK/JNK, and AP-1/NF-?B activation were examined via Western blotting, a flow cytometric analysis, and luciferase assay. In pharmacological studies, the ROS scavenger, N-acetyl cysteine (NAC), the NADPH oxidase inhibitor, diphenylene iodide (DPI), and mitogen-activated protein kinase (MAPK) inhibitors (U0126 and SP600125) were applied to investigate the mechanism. RESULTS: We found that P. acnes exposures increased iNOS/NO and COX-2/PGE(2) expression in RAW264.7, J774A.1, and peritoneal macrophages via a MOI-dependent manner. Increased ROS production, ERK/JNK protein phosphorylation, and elevated AP-1/NF-?B luciferase activity are identified in P. acnes-induced iNOS/NO and COX-2/PGE(2) production. Additionally, hispolon but not its analogs, hispolon methylether or dehydroxyhispolon, showed significant inhibition of P. acnes-induced iNOS/NO and COX-2/PGE(2) production, indicating an important role of OH at C5 for hispolon's inhibition of P. acnes-induced inflammatory events in macrophages. CONCLUSION: ROS-dependent stimulation of ERK, JNK, NF-?B, and AP-1 activation contributes to P. acnes-induced iNOS/NO and COX-2/PGE(2) in macrophages, and chemicals such as hispolon possessing ability to block iNOS/NO and COX-2/PGE(2) production reserve potential to be further developed for treatment of the early phase of inflammation elicited by P. acnes.

PMID: 23178030 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001