Diesel exhaust particles suppress in vivo IFN-gamma production by inhibiting cytokine effects on NK and NKT cells.
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-alpha secretion, and decreased basal levels of IFN-gamma. When injected with or before LPS, DEP had little effect on the LPS-induced TNF-alpha responses, but partially inhibited the LPS-induced IL-10 response and strongly inhibited the LPS-induced IFN-gamma response. DEP also inhibited the IFN-gamma 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-gamma production by splenic NK and NKT cells. In contrast, DEP failed to inhibit the IFN-gamma response by anti-CD3 mAb-activated NKT cells. Taken together, these observations suggest that DEP inhibit Toll-like receptor ligand-induced IFN-gamma responses by interfering with cytokine signaling pathways that stimulate NK and NKT cells to produce IFN-gamma. Our observations also suggest that DEP may promote a Th2 response by stimulating production of inflammatory cytokines while simultaneously inhibiting production of IFN-gamma, and raise the possibility that the same mechanisms contribute to the association between DEP exposure and asthma.
Finkelman
Fred D
FD
Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. ffinkelman@pol.net
Yang
Mingyan
M
Orekhova
Tatyana
T
Clyne
Erin
E
Bernstein
Jonathan
J
Whitekus
Michael
M
Diaz-Sanchez
David
D
Morris
Suzanne C
SC
D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors; D001335:Vehicle Emissions / Q000633:toxicity*
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D001335:Vehicle Emissions; D007371:Interferon-gamma