Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action.
BACKGROUND
H1-receptor antagonists are often effective in the treatment of allergic disorders such as atopic dermatitis. Cetirizine, a putative H1-receptor antagonist, has recently been shown to have anti-inflammatory properties through the inhibition of leucocyte recruitment and activation, and by the reduction of ICAM-1 expression on keratinocytes.


OBJECTIVE
To further elucidate the anti-inflammatory properties of cetirizine, we first examined its effects on antigen-induced eosinophilia and neutrophila in vivo. We then examined the anti-inflammatory effects of cetirizine on a human keratinocyte A431cell line.


METHODS
Mice were sensitized subcutaneously with ragweed pollen and were challenged intraperitoneally with the allergen. Cetirizine diluted in sterile water (0-20 mg/kg) or only sterile water was administered orally. Peritoneal cells were obtained at 8 and 24 h after challenge. The eosinophilia and neutrophilia induced by ragweed pollen extract were quantitated. Macrophage migration inhibitory factor (MIF), macrophage inflammatory protein 2 (MIP-2) and eotaxin contents of peritoneal fluid were also measured by mouse ELISA. The effects of cetirizine on MIF-induced IL-8 production in A431 cells were examined by ELISA. The effects of cetirizine on MIF expression and production in A431 cells were examined by human MIF ELISA and Northern blot analysis.


RESULTS
Eosinophilia and neutrophilia induced by ragweed pollen extract were found to be significantly reduced in cetirizine-treated mice (20 mg/kg). MIF, a pleuripotent cytokine, was significantly decreased at 8 and 24 h in the peritoneal fluid by cetirizine treatment. MIP-2 and eotaxin were also decreased 8 and 24 h, respectively, after challenge in the peritoneal fluid with cetirizine treatment. MIF stimulates IL-8 production in A431 cells. We found that MIF production in A431 cells was inhibited by 10 microm cetirizine. Consistent with this, cetirizine significantly inhibited MIF-induced IL-8 production.


CONCLUSIONS
These results suggest that cetirizine exerts its anti-inflammatory effects by inhibiting MIF as well as IL-8 production, such as those involved in inflammatory allergic skin disease, suggesting a broad spectrum of action beyond its mere H1-receptor-antagonistic function.
Shimizu
T
T
Departments of Dermatology Molecular Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Nishihira
J
J
Watanabe
H
H
Abe
R
R
Ishibashi
T
T
Shimizu
H
H
D000485:Allergens / Q000008:administration & dosage; D031164:Ambrosia / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D017332:Cetirizine / Q000494:pharmacology*; D054413:Chemokine CCL11; D054426:Chemokine CXCL2; D019742:Chemokines, CC / Q000032:analysis; D004802:Eosinophilia / Q000276:immunology / Q000517:prevention & control*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis; D015603:Keratinocytes / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000032:analysis; D009504:Neutrophils / Q000276:immunology; D011058:Pollen
D000485:Allergens; D000893:Anti-Inflammatory Agents; C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D054426:Chemokine CXCL2; D019742:Chemokines, CC; D006634:Histamine H1 Antagonists; D016209:Interleukin-8; D008263:Macrophage Migration-Inhibitory Factors; D015846:Monokines; D017332:Cetirizine