In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma.
DNA containing unmethylated CpG motifs is intrinsically immunostimulatory, inducing the production of a variety of cytokines and chemokines by immune cells. The strong Th1 response triggered by CpG oligodeoxynucleotide (ODN) inhibits the development of Th2-mediated allergic asthma in mice. This work documents that CpG ODN-induced IL-12 production plays a critical role in this process, because intrapulmonary CpG ODN inhibits allergic inflammation in wild-type but not IL-12(-/-) mice. CpG ODN rapidly localized to alveolar macrophages (AM), thereby triggering the phosphorylation of p38 mitogen-activated protein kinase (MAP kinase). AM cultured with CpG but not control ODN up-regulated IL-12 p40 expression and release, and these effects were blocked by the highly specific p38 MAP kinase inhibitor SB202190. Intrapulmonary administration of this inhibitor blocked the ability of CpG ODN to produce IL-12 in the lungs and reversed the anti-inflammatory effects of CpG ODN on allergic lung inflammation. These findings indicate that IL-12 production by AM is stimulated by intrapulmonary CpG ODN administration through a p38 MAP kinase-dependent process, and IL-12 is a key cytokine that mediates CpG ODN-induced protection against allergic lung inflammation.
Choudhury
Barun K
BK
NIH Asthma and Allergic Diseases Research Center, University of Texas Medical Branch, Galveston, TX 77555, USA.
Wild
James S
JS
Alam
Rafeul
R
Klinman
Dennis M
DM
Boldogh
Istvan
I
Dharajiya
Nilesh
N
Mileski
William J
WJ
Sur
Sanjiv
S
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053762:Interleukin-12 Subunit p40; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; C408982:CPG-oligonucleotide; D004791:Enzyme Inhibitors; D007093:Imidazoles; D053762:Interleukin-12 Subunit p40; D009838:Oligodeoxyribonucleotides; D021122:Protein Subunits; D011725:Pyridines; D012333:RNA, Messenger; D018664:Interleukin-12; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole