title: Dipyrone & 2,5-dimethylcelecoxib suppress Th2-related chemokine production in monocyte.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.forename: Jeng-Chuan
authors.initials: JC
authors.lastname: Shiang
authors.forename: Ren-Long
authors.initials: RL
authors.lastname: Jan
authors.forename: Ming-Kai
authors.initials: MK
authors.lastname: Tsai
authors.forename: Chong-Chao
authors.initials: CC
authors.lastname: Hsieh
authors.forename: Hsuan-Fu
authors.initials: HF
authors.lastname: Kuo
authors.forename: Chang-Hung
authors.initials: CH
authors.lastname: Kuo
authors.forename: San-Nan
authors.initials: SN
authors.lastname: Yang
authors.forename: Ming-Yii
authors.initials: MY
authors.lastname: Huang
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University Hospital; Department of Pediatrics, Faculty of Medicine; Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University; Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.
authors.forename: Chih-Hsing
authors.initials: CH
authors.lastname: Hung
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D054402:Chemokine CCL1 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D004177:Dipyrone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D009000:Monocytes / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C506698:2,5-dimethylcelecoxib; D000894:Anti-Inflammatory Agents, Non-Steroidal; C065971:CCL1 protein, human; C114753:CXCL10 protein, human; D054402:Chemokine CCL1; D054357:Chemokine CXCL10; D018925:Chemokines; D011720:Pyrazoles; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D004177:Dipyrone; D051722:ADAM Proteins; C090222:ADAM11 protein, human