Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain.
New insights into the biological properties of cyclooxygenase-2 (COX-2) and its response pathway challenge the hypothesis that COX-2 is simply pro-inflammatory and inhibition of COX-2 solely prevents the development of inflammation and ameliorates inflammatory pain. The present study performed a comprehensive analysis of gene/protein expression induced by a selective inhibitor of COX-2, rofecoxib, compared with a non-selective COX inhibitor, ibuprofen, and placebo in a clinical model of acute inflammatory pain (the surgical extraction of impacted third molars) using microarray analysis followed by quantitative RT-PCR verification and Western blotting. Inhibition of COX-2 modulated gene expression related to inflammation and pain, the arachidonic acid pathway, apoptosis/angiogenesis, cell adhesion and signal transduction. Compared to placebo, rofecoxib treatment increased the gene expression of ANXA3 (annexin 3), SOD2 (superoxide dismutase 2), SOCS3 (suppressor of cytokine signaling 3) and IL1RN (IL1 receptor antagonist) which are associated with inhibition of phospholipase A(2) and suppression of cytokine signaling cascades, respectively. Both rofecoxib and ibuprofen treatment increased the gene expression of the pro-inflammatory mediators, IL6 and CCL2 (chemokine C-C motif ligand 2), following tissue injury compared to the placebo treatment. These results indicate a complex role for COX-2 in the inflammatory cascade in addition to the well-characterized COX-dependent pathway, as multiple pathways are also involved in rofecoxib-induced anti-inflammatory and analgesic effects at the gene expression level. These findings may also suggest an alternative hypothesis for the adverse effects attributed to selective inhibition of COX-2.
Wang
Xiao-Min
XM
NINR/NIH, Bethesda, MD 20892, USA.
Wu
Tian-Xia
TX
Hamza
May
M
Ramsay
Edward S
ES
Wahl
Sharon M
SM
Dionne
Raymond A
RA
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage*; D007155:Immunologic Factors / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D007783:Lactones / Q000008:administration & dosage*; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000008:administration & dosage*
D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D007155:Immunologic Factors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D007052:Ibuprofen