MACROPHAGE ACTIVATION BY POLYCYCLIC AROMATIC-HYDROCARBONS - EVIDENCE FOR THE INVOLVEMENT OF STRESS-ACTIVATED PROTEIN-KINASES, ACTIVATOR PROTEIN-1, AND ANTIOXIDANT RESPONSE ELEMENTS

Polycyclic aromatic hydrocarbans (PAH) contained in fossil fuel combus tion particles enhance the allergic response to common environmental A gs, A key question is: what are molecular pathways in the immune syste m by which PAN and conversion products drive allergic inflammation? Ci rcumstantial evidence suggests that macrophages are involved in PAM-in duced responses, We demonstrate that a representative PAN, beta-naptho flavone (BNF), and a representative quinone metabolite, tert-butylhydr oxyquinone (tBHQ), induce Jun kinase and p38 mitogen-activated protein kinase activities in parallel with the generation of activates protei n-1 (AP-1) mobility shift complexes in THP-1 and RAW264.7 macrophage c ell lines. Activation of mitogen-activated protein kinases was depende nt on generation of oxidative stress, and could be inhibited by N-acet ylcysteine. Another genetic response pathway linked to PAH is the anti oxidant response element (ARE), which regulates expression of detoxify ing enzymes, BNF and tBHQ activated a human ARE (hARE) reporter gene i n RBW264.7 cells. Interestingly, bacterial lipopolysaccharide also ind uced hARE/chloramphenicol acetyltransferase activity. While the hARE f ore, GTGACTCAGC, contains a consensus BP-1 sequence (underlined), AP-1 was not required for hARE activation. This suggests that PAH and thei r conversion products operate via ARE-specific transcription factors i n the immune system. BNF and tBHQ did, however, induce AP-1 binding to the hARE, while constitutively active Jun kinase interfered in hARE/c hloramphenicol acetyltransferase activation, This suggests that AP-1 p roteins negatively regulate the hARE. These data establish important a ctivation pathways for PAH in the immune system and provide us with ta rgets to modulate the effect of environmental pollutants on allergic i nflammation.