15-lipoxygenase metabolites play an important role in the development of a T-helper type 1 allergic inflammation induced by double-stranded RNA.

Abstract

BACKGROUND:

We recently demonstrated that the T-helper type 1 (Th1) immune response plays an important role in the development of non-eosinophilic inflammation induced by airway exposure of an allergen plus double-stranded RNA (dsRNA). However, the role of lipoxygenase (LO) metabolites in the development of Th1 inflammation is poorly understood.

OBJECTIVE:

To evaluate the role of LO metabolites in the development of Th1 inflammation induced by sensitization with an allergen plus dsRNA.

METHODS:

A Th2-allergic inflammation mouse model was created by an intraperitoneal injection of lipopolysaccharide-depleted ovalbumin (OVA, 75 microg) and alum (2 mg) twice, and the Th1 model was created by intranasal application of OVA (75 microg) and synthetic dsRNA [10 microg of poly(I : C)] four times, followed by an intranasal challenge with 50 microg of OVA four times. The role of LO metabolites was evaluated using two approaches: a transgenic approach using 5-LO(-/-) and 15-LO(-/-) mice, and a pharmacological approach using inhibitors of cysteinyl leucotriene receptor-1 (cysLTR1), LTB4 receptor (BLT1), and 15-LO.

RESULTS:

We found that the Th1-allergic inflammation induced by OVA+dsRNA sensitization was similar between 5-LO(-/-) and wild-type (WT) control mice, although Th2 inflammation induced by sensitization with OVA+alum was reduced in the former group. In addition, dsRNA-induced Th1 allergic inflammation, which is associated with down-regulation of 15-hydroxyeicosateraenoic acids production, was not affected by treatment with cysLTR1 or BLT1 inhibitors, whereas it was significantly lower in 12/15-LO(-/-) mice compared with WT control mice. Moreover, dsRNA-induced allergic inflammation and the recruitment of T cells following an allergen challenge were significantly inhibited by treatment with a specific 15-LO inhibitor (PD146176).

CONCLUSION:

15-LO metabolites appear to be important mediators in the development of Th1-allergic inflammation induced by sensitization with an allergen plus dsRNA. Our findings suggest that the 15-LO pathway is a novel therapeutic target for the treatment of virus-associated asthma characterized by Th1 inflammation.

• Authors: S G Jeon, H-G Moon, Y-S Kim, J-P Choi, T-S Shin, S-W Hong, Y-M Tae, S-H Kim, Z Zhu, Y S Gho, Y-K Kim
• Journal: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology (Clin Exp Allergy) Vol. 39 Issue 6 Pg. 908-17 (Jun 2009) ISSN: 1365-2222 [Electronic] England
• PMID: 19260872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene
• Acetates
• Allergens
• Alum Compounds
• Cyclopropanes
• Fatty Alcohols
• Fluorenes
• Glycols
• Leukotriene Antagonists
• Lipoxygenase Inhibitors
• Ltb4r1 protein, mouse
• Quinolines
• RNA, Double-Stranded
• Receptors, Leukotriene
• Receptors, Leukotriene B4
• Sulfides
• ovalbumin-alum
• U 75302
• Ovalbumin
• Arachidonate 15-Lipoxygenase
• Arachidonate 5-Lipoxygenase
• montelukast
• Poly I-C

Topics

• Acetates (pharmacology)
• Allergens (immunology)
• Alum Compounds (pharmacology)
• Animals
• Arachidonate 15-Lipoxygenase (genetics, immunology, metabolism)
• Arachidonate 5-Lipoxygenase (genetics, immunology, metabolism)
• Cyclopropanes
• Disease Models, Animal
• Fatty Alcohols (pharmacology)
• Fluorenes (pharmacology)
• Glycols (pharmacology)
• Hypersensitivity (enzymology, immunology)
• Inflammation (immunology, metabolism)
• Leukotriene Antagonists (pharmacology)
• Lipoxygenase Inhibitors
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Ovalbumin (pharmacology)
• Poly I-C (immunology)
• Quinolines (pharmacology)
• RNA, Double-Stranded (immunology)
• Receptors, Leukotriene (drug effects, immunology, metabolism)
• Receptors, Leukotriene B4 (antagonists & inhibitors, immunology, metabolism)
• Sulfides
• Th1 Cells (enzymology, immunology)
• Th2 Cells (enzymology, immunology)