Suppressive effects of ketotifen on Th1- and Th2-related chemokines of monocytes.
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 monocytes in vitro and ex vivo. Ketotifen (5-50 microM) 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.
Hung
Chih-Hsing
CH
Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Suen
Jau-Ling
JL
Hua
Yi-Ming
YM
Chiang
Wen
W
Chang
Hui-Chiu
HC
Chen
Chun-Nan
CN
Jong
Yuh-Jyh
YJ
D018926:Anti-Allergic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007665:Ketotifen / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D018926:Anti-Allergic Agents; D018925:Chemokines; D007166:Immunosuppressive Agents; D007665:Ketotifen