Dipyrone & 2,5-dimethylcelecoxib suppress Th2-related chemokine production in monocyte.

ABSTRACT

BACKGROUND & OBJECTIVES: Selective cyclooxygenase-2 (COX-2) inhibitor is a form of thnon steroidal anti-inflammatory drug (NSAID) and is commonly used in autoimmune and rheumatic diseases to control inflammation and alleviate pain. Tumour necrosis factor-alpha (TNF-α) production and an imbalance of T helper 1 (Th1)/Th2 contribute to the pathogenesis of autoimmune and also anti-tumour activity. Dipyrone is a NSAID used to treat pain worldwide. The celecoxib analogue, 2,5-dimethylcelecoxib (DMC), lacks COX-2 inhibitory activity but exhibits anti-tumour properties. However, the effects and the mechanisms of dipyrone and 2,5-dimethylcelecoxib on tumour necrosis factor (TNF)-α and Th1- and Th2-related chemokines in monocytes remain poorly defined. This study was carried out to investigate the effects of dipyrone and 2,5-dimethylcelecoxib on the expression of Th1 (IP-10) and Th2 (I-309 and MDC) and TNF-α in human monocytes and the associated intracellular mechanism. METHODS: THP-1 cells and peripheral blood mononuclear cells (PBMCs) were pre-treated with dipyrone (10(-9)-10(-4) M) and 2,5-dimethylcelecoxib (10(-9)-10(-5) M) 2 h before lipopolysaccharide (LPS) stimulation. Cell supernatant was collected 24 h after LPS stimulation. TNF-α, I-309, MDC and IP-10 concentrations of cell supernatants were determined using ELISA. Intracellular signaling was evaluated by w0 estern blot. RESULTS: Dipyrone and 2,5-dimethylcelecoxib downregulated LPS-induced Th2-related chemokine I-309 and macrophage derived chemokine (MDC) production. Only high dose of 2,5-dimethylcelecoxib (10(-5) M), but not dipyrone downregulated LPS-induced IP-10. Only very high dose of 2,5-dimethylcelecoxib had effect on LPS-induced TNF-α expression in PBMCs. Dipyrone and 2,5-dimethylcelecoxib suppressed LPS-induced p65 and JNK MAPK (C-Jun N-terminal kinase mitogen activated protein kinase). expression. INTERPRETATION & CONCLUSIONS: Dipyrone and 2,5-dimethylcelecoxib downregulated LPS-induced Th2-related chemokine I-309 and MDC in THP-1 cells. The suppressive effect on Th2-related chemokine I-309 and MDC may involve the downregulation of LPS-induced JNK and p65 expression.