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.
Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. ffinkelman@pol.net
Fred D
FD
Finkelman
Mingyan
M
Yang
Tatyana
T
Orekhova
Erin
E
Clyne
Jonathan
J
Bernstein
Michael
M
Whitekus
David
D
Diaz-Sanchez
Suzanne C
SC
Morris
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