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DIESEL EXHAUST PARTICLES SUPRESS LPS-STIMULATED PRODUCTION OF PGE2 IN HUMAN ALVEOLAR MACHROPHAGES: ROLE OF P38 MAPK AND ERK PATHWAYS
Citation:
Madden, M. C., S E. Becker, AND S. Mundandhara. DIESEL EXHAUST PARTICLES SUPRESS LPS-STIMULATED PRODUCTION OF PGE2 IN HUMAN ALVEOLAR MACHROPHAGES: ROLE OF P38 MAPK AND ERK PATHWAYS. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
Numerous studies have reported association between exposure to ambient levels of particulate matter (PM) and adverse health effects, which include respiratory and cardiovascular effects. Diesel exhaust particles (DEP) compose a significant fraction of PM in some areas. Alveolar macrophages (AM), the key players in pulmonary host defense mechanisms, functions by activating and releasing soluble mediators such as cytokines and prostanoids. This study was designed to investigate the effect of DEP on human AM responsiveness to LPS by monitoring the release of PGE2 and also to study the signal transduction pathways involved in the expression of cyclooxygenase. AM were exposed in vitro to Standard Reference Material 2975, SRM 1650, SRM 1975 (dichloromethane extract of SRM 2975) (SRMs from NIST) or carbon black (CB) for 24hr, and subsequently incubated with LPS (lng/ml) for 24hr. DEPs, but not CB, suppressed the release of PGE2 by LPS-stimulated AM. This suppression is significant after 4h of LPS stimulation. mRNA expression of COX-2 was not affected by all DEP treatment at 2h of LPS treatment, but there was a decreased COX-2 mRNA expression (>50%) after 4h of LPS treatment, suggesting a feedback inhibition. However, COX-2 protein levels were equivalent in LPS and DEPs exposed AM. Further mechanistic studies to investigate the effect of DEPs on p38 MAPK and ERK signaling pathways showed that DEPs alone (24 hr) did not inhibit the phosphorylation of p38 or p42. However, DEP exposure induced a decrease in phosphorylated p38 and p42 (vs vehicle) with LPS stimulation. The data indicate DEPs suppress the ability of AM to produce PGE2 in response to LPS, despite having no effect on the COX-2 protein expression. The data suggest that organic extract was capable of inducing these responses without the particle core. Alteration of macrophage signaling pathways may play a role in some PM-induced health effects. [This abstract may not represent official EPA policy.