067 Diesel exposure favors Th2 cell recruitment by mononuclear cells from nonatopic subjects by differentially regulating CCL18/PARC and CXCL10/IP-10 production

Introduction Allergie asthma is a Th2-mediated inflammatory airway disorder. Its prevalence has strongly increased during the last 20 years, in part related to pollution exposure. Cell recruitment to inflammatory sites is orchestrated by chemokines and their recep-tors such as recruitment of Th2 cells by MDC and 1-309 through CCR4 and CCR8 respectively, or of Thl cells by IP-10 and MIG through CXCR3. Some studies showed that diesel exhaust particles (DEP), especially their associated polyaromatic hydrocarbons (DEP-PAH) can exacerbate the allergie reaction. Much less is known about their potential capacity to induce a Th2-type allergie reaction in non allergie subjects. To address this fundamental question, we investigated the kinetic effect of DEP-PAH on chemokines associated with Thl(IP-10, MIG) and Th2 (MDC, 1-309) recruitment, or induced by Th2 cytokines (PARC). Methods Peripheral blood mononuclear cells (PBMC) from 8 healthy nonatopic subjects were cultured with 25, 50 and 100 ng/ml of DEP-PAH and solvent CH2C12 for 18, 24 and 48 hours. Neu-tralizing anti-IL-4, anti-IL-10 and anti-IL-13 mAbs were used to identify the signaling pathway involved in PARC enhancement. Release of IP-10, MIG, MDC, 1-309, PARC, IL-4, IL-10 and IL-13 was measured by ELISA. mRNA expression of PARC and IP-10 was examined by semiquantitative RT-PCR. Chemotaxis assays were performed on in vitro polarized Th 1 and Th2 cells to evaluate resulting biologie chemotactic activity of supernatants. Results Diesel exposure did not modify release of MDC, 1-309 and MIG. In contrast, it decreased IP-10 and increased PARC at both protein and mRNA level. The functional effect of chemokine variations resulted in enhanced chemotaxis of Th2 cells but not Thl cells. Th2 cell attraction was inhibited by neutralizing anti-PARC mAb. Neutralizing antibodies against IL-4 and IL-10 had no effect on PARC production while neutralizing anti-IL-13 mAb partly inhibited its release. Conclusion DEP-PAH could regulate in non atopic subjects chemokines favoring the recruitment of Th2 cells, suggesting that diesel exposure may be involved in the genesis of allergie diseases. Additionally, IL-13 mediates at least one mechanism involved in PARC enhancement by DEP-PAH exposure.