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Diesel Exhaust Particles Suppress In Vivo IFN- Production by Inhibiting Cytokine Effects on NK and NKT Cells¹

Fred D. Finkelman^2,*,,, Mingyan Yang^*, Tatyana Orekhova^*, Erin Clyne^*, Jonathan Bernstein^*, Michael Whitekus, David Diaz-Sanchez and Suzanne C. Morris^*,

^* Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; Cincinnati Veterans Administration Medical Center, Cincinnati, OH 45220; and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095

Diesel exhaust particles (DEP) have strong, selective Th2 adjuvant activity when inhaled with conventional Ags. We used a novel technique for measuring in vivo cytokine production to investigate possible mechanisms by which DEP might promote a Th2 response. Injection of DEP i.p. stimulated IL-6 secretion, but failed to increase IL-4, IL-10, or TNF- secretion, and decreased basal levels of IFN-. When injected with or before LPS, DEP had little effect on the LPS-induced TNF- responses, but partially inhibited the LPS-induced IL-10 response and strongly inhibited the LPS-induced IFN- response. DEP also inhibited the IFN- responses to IL-12, IL-12 plus IL-18, IL-2, and poly(I · C). DEP treatment had little effect on the percentages of NK and NKT cells in the spleen, but inhibited LPS-induced IFN- production by splenic NK and NKT cells. In contrast, DEP failed to inhibit the IFN- response by anti-CD3 mAb-activated NKT cells. Taken together, these observations suggest that DEP inhibit Toll-like receptor ligand-induced IFN- responses by interfering with cytokine signaling pathways that stimulate NK and NKT cells to produce IFN-. Our observations also suggest that DEP may promote a Th2 response by stimulating production of inflammatory cytokines while simultaneously inhibiting production of IFN-, and raise the possibility that the same mechanisms contribute to the association between DEP exposure and asthma.

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