It has been proposed that the pro-inflammatory catalytic activity of cyclooxygenase-2 (COX-2) plays a key role in the aging process. However, it remains unclear whether the COX-2 activity is a causal factor for aging and whether COX-2 inhibitors could prevent aging. We here examined the effect of COX-2 inhibitors on aging in the intrinsic skin aging model of hairless mice. We observed that among two selective COX-2 inhibitors and one non-selective COX inhibitor studied, only NS-398 inhibited skin aging, while celecoxib and aspirin accelerated skin aging. In addition, NS-398 reduced the expression of p53 and p16, whereas celecoxib and aspirin enhanced their expression. We also found that the aging-modulating effect of the inhibitors is closely associated with the expression of type I procollagen and caveolin-1. These results suggest that pro-inflammatory catalytic activity of COX-2 is not a causal factor for aging at least in skin and that COX-2 inhibitors might modulate skin aging by regulating the expression of type I procollagen and caveolin-1.
Animals ; Aspirin/administration & dosage ; Catalysis ; Caveolin 1/genetics/metabolism ; Collagen Type I/genetics/metabolism ; *Cyclooxygenase 2/metabolism/physiology ; Cyclooxygenase 2 Inhibitors/*administration & dosage ; Gene Expression Regulation ; Mice ; Nitrobenzenes/*administration & dosage ; Pyrazoles/administration & dosage ; Skin Aging/*drug effects/physiology ; Sulfonamides/*administration & dosage ; Tumor Suppressor Protein p53/genetics/metabolism

Myeloid-derived suppressor cells (MDSCs) play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 (Cox-2) contributes to immune disorder in trauma and infection via production of prostaglandin E2. However, the role of Cox-2 in the accumulation and function of MDSCs after traumatic stress has not been fully elucidated. In the present study, we treated murine trauma model with NS398, a selective Cox-2 inhibitor. Then the percentages of CD11b+/Gr-1+ cells, proliferation and apoptosis of CD4+ T cells were determined. Arginase activity and arginase-1 (Arg-1) protein expression of splenic CD11b+/Gr-1+ cells, and delayed-type hypersensitivity (DTH) response were analyzed. The results showed that Cox-2 blockade significantly decreased the percentages of CD11b+/Gr-1+ cells in the spleen and bone marrow 48 and 72 h after traumatic stress. NS398 inhibited arginase activity and down-regulated the Arg-1 expression of splenic CD11b+/Gr-1+ cells. Moreover, NS398 could promote proliferation and inhibit apoptosis of CD4+ T cells. It also restored DTH response of traumatic mice. Taken together, our data revealed that Cox-2 might play a pivotal role in the accumulation and function of MDSC after traumatic stress.
Animals ; Apoptosis ; drug effects ; Arginase ; biosynthesis ; CD11b Antigen ; biosynthesis ; CD4-Positive T-Lymphocytes ; drug effects ; metabolism ; Cell Proliferation ; drug effects ; Cyclooxygenase 2 ; biosynthesis ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; Gene Expression Regulation ; drug effects ; Humans ; Mice ; Myeloid Progenitor Cells ; metabolism ; pathology ; Nitrobenzenes ; administration & dosage ; Stress Disorders, Traumatic ; drug therapy ; genetics ; pathology ; Sulfonamides ; administration & dosage

OBJECTIVESTo observe the effects of NS-398 on proliferation of hepatic stellate cells (HSCs) in vitro, and to investigate the possible molecule mechanism.

METHODSHSCs were incubated with different concentrations of NS-398. The effects of NS-398 on cell proliferation was detected by MTT colormetric assay. The cell cycle of HSCs was analyzed by Flow Cytometry (FCM), cyclooxygenase-2 (COX-2) and proliferating cell nuclear antigen (PCNA) proteins in HSCs were detected by immunocytochemistry.

RESULTSAdministration of 20-160 micromol/L NS-398 significantly inhibited HSCs proliferation in dose-dependent manner compared with the control group (P less than 0.01). After treated with NS-398 at concentrations of 90, 120, and 150 micromol/L for 48 h, the number of HSCs in G(2)/M phase increased and the number of HSCs in G(0)/G(1) phase decreased (P less than 0.05); Incubated with 120 micromol/L NS-398 for 48 h, percentage of masculine cell of PCNA was 28.91%+/-0.11%, which was significantly lower than that of the control group (85.99%+/-0.13%) (P less than 0.01). Percentage of masculine cell of COX-2 was 13.80%+/-0.43%, which was not significantly different from that of the control group (14.07%+/-0.59%) (P more than 0.05).

CONCLUSIONSNS-398 could inhibit the proliferation of HSC-T6 and arrest HSCs in G2/M phase. Down-regulation of PCNA protein may partially accounted for the proliferation inhibition effect on HSCs induced by NS-398.

Animals ; Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Cell Line ; Cell Proliferation ; drug effects ; Cyclooxygenase 2 ; metabolism ; Cyclooxygenase Inhibitors ; administration & dosage ; pharmacology ; Dose-Response Relationship, Drug ; Flow Cytometry ; Hepatic Stellate Cells ; drug effects ; metabolism ; Liver Cirrhosis ; pathology ; prevention & control ; Nitrobenzenes ; pharmacology ; Proliferating Cell Nuclear Antigen ; metabolism ; Rats ; Sulfonamides ; pharmacology