Public Health Resources
Date of this Version
8-2007
Abstract
Background: Organic dust exposure results in an inflammatory response that attenuates over time, but repetitive exposures can result in chronic respiratory diseases. Mechanisms underlying this modulated response are not clear.
Objective: This study investigated the effects of repeat versus single organic dust exposure–induced inflammatory mediators and protein kinase C (PKC) activity in monocytes.
Methods: Settled organic dust was obtained from swine confinement facilities. Promonocytic THP-1 cells and human peripheral blood monocytes were pretreated with or without dust extract and then restimulated. Culture supernatants were evaluated for TNF-α, IL-6, CXCL8, and IL-10. Responses were compared with endotoxin-depleted dust, LPS, and peptidoglycan. PKC isoform (α, δ, ε, ζ) activation was evaluated by direct kinase activity. PKC isoform inhibitors’ effects on TNF-a secretion were studied.
Results: Single exposure to organic dust stimulated monocyte secretion of TNF-α, IL-6, CXCL8, and IL-10 compared with unstimulated cells. TNF-α and IL-6 were diminished in pretreated cells restimulated with dust. Secretion of CXCL8 and IL-10 remained persistently elevated. TNF-α responses were retained after marked depletion of endotoxin. Dust exposure induced significant PKC α, δ, ε, and ζ activation, peaking at 30 to 60 minutes. PKC isoform activation was attenuated in repeat exposed cells. Inhibition of PKCa and PKCe reduced dust-induced TNF-α secretion.
Conclusion: Repeat organic dust exposure modulated inflammatory mediator production in monocytes independent of endotoxin. The inability of PKC to be reactivated may account for this observation.
Clinical implications: Targeting PKC and specific mediators associated with repetitive organic dust exposure may result in novel therapeutic strategies.
Comments
Published in Journal of Allergy and Clinical Immunology 120:2 (August 2007), pp. 366-373.