Repeat organic dust exposure-induced monocyte inflammation is associated with protein kinase C activity.
Poole-JA; Wyatt-TA; Von Essen-SG; Hervert-J; Parks-C; Mathisen-T; Romberger-DJ
J Allergy Clin Immunol 2007 Aug; 120(2):366-373
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-alpha, IL-6, CXCL8, and IL-10. Responses were compared with endotoxin-depleted dust, LPS, and peptidoglycan. PKC isoform (alpha, delta, epsilon, zeta) activation was evaluated by direct kinase activity. PKC isoform inhibitors' effects on TNF-alpha secretion were studied. RESULTS: Single exposure to organic dust stimulated monocyte secretion of TNF-alpha, IL-6, CXCL8, and IL-10 compared with unstimulated cells. TNF-alpha and IL-6 were diminished in pretreated cells restimulated with dust. Secretion of CXCL8 and IL-10 remained persistently elevated. TNF-alpha responses were retained after marked depletion of endotoxin. Dust exposure induced significant PKC alpha, delta, epsilon, and zeta activation, peaking at 30 to 60 minutes. PKC isoform activation was attenuated in repeat exposed cells. Inhibition of PKCalpha and PKCepsilon reduced dust-induced TNF-alpha 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.
Organic-dusts; Dusts; Dust-exposure; Dust-particles; Respiratory-system-disorders; Respiration; Humans; Men; Women; Diseases; Pharmacology; Etiology; Animals; Cellular-function; Cellular-reactions; Cell-biology; Cell-function; Metabolism;
Author Keywords: Monocyte; adaptation; organic dust; swine; cytokines; inflammation; protein kinase C
Jill A. Poole, MD, Pulmonary, Critical Care, Sleep and Allergy Section, University of Nebraska Medical Center, 985300 The Nebraska Medical Center, Omaha, NE 68198-5300
Agriculture, Forestry and Fishing
Journal of Allergy and Clinical Immunology
University of Nebraska