Suppressive effects of ketotifen on Th1‐ and Th2‐related chemokines of monocytes

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Abstract
Ketotifen is a mast cell stabilizer and useful in younger children with allergic diseases such as asthma and allergic rhinitis. Macrophage‐derived chemokine (MDC) is a T‐helper cell type 2 (Th2)‐related chemokine involved in recruitment of Th2 cells toward allergen‐challenged inflammation. However, the Th1‐related chemokines, interferon‐inducible protein 10 (IP‐10) /CXCL10, and the monokine induced by interferon‐gamma (MIG)/CXCL9 are also important in allergen‐induced asthma in animal models. We investigated the effects of ketotifen on the expression of Th1‐ and Th2‐related chemokines of human monocytesin vitroandex vivo. Ketotifen (5–50 μm) significantly down‐regulated lipopolysaccharide (LPS)‐induced MDC, MIG and IP‐10 (p < 0.05, each comparison) in THP‐1 cells and human primary monocytes in a dose‐dependent manner. SB203580 [p38‐mitogen‐activated protein kinase (MAPK) inhibitor] suppressed LPS‐induced MDC and IP‐10 expression, and PD98059 (ERK–MAPK inhibitor) could only suppress LPS‐induced IP‐10, but not MDC expression. LPS‐induced pp38 and p‐ERK expression of THP‐1 monocytic cells was suppressed by ketotifen. These data demonstrate that ketotifen is effective in down‐regulating LPS‐induced MDC, MIG and IP‐10, which play important roles in the pathogenesis of airway inflammation. The suppressive effect on MDC and IP‐10 may, at least in part, involve the down‐regulation of LPS‐induced p38 and ERK–MAPK expression.