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.

• Authors: Jeng-Chuan Shiang, Ren-Long Jan, Ming-Kai Tsai, Chong-Chao Hsieh, Hsuan-Fu Kuo, Chang-Hung Kuo, San-Nan Yang, Ming-Yii Huang, Li-Chen Chen, Chih-Hsing Hung
• Journal: The Indian journal of medical research (Indian J Med Res) Vol. 140 Issue 1 Pg. 109-15 (Jul 2014) ISSN: 0971-5916 [Print] India
• PMID: 25222785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2,5-dimethylcelecoxib
• Anti-Inflammatory Agents, Non-Steroidal
• CCL1 protein, human
• CXCL10 protein, human
• Chemokine CCL1
• Chemokine CXCL10
• Chemokines
• Pyrazoles
• Sulfonamides
• Tumor Necrosis Factor-alpha
• Tumor Suppressor Proteins
• Dipyrone
• ADAM Proteins
• ADAM11 protein, human

Topics

• ADAM Proteins (metabolism)
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Blotting, Western
• Chemokine CCL1 (metabolism)
• Chemokine CXCL10 (metabolism)
• Chemokines (metabolism)
• Dipyrone (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation (drug effects, immunology)
• Humans
• Monocytes (drug effects)
• Pyrazoles (pharmacology)
• Sulfonamides (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• Tumor Suppressor Proteins (metabolism)