HSP suggesting the suppressive effect of TFM C on neutrophil recruitment

Effect of TFM C on neutrophil recruitment, mice were treated with TFM C, HSP celecoxib or control vehicle, and thioglycollate was injected intraperitoneally. Leukocyte cell numbers in the peritoneal cavity four hours after thioglycollate injection were comparable between control and celecoxib treated groups. However, the peritoneal infiltrating cell numbers were reduced in mice treated with TFM C, suggesting the suppressive effect of TFM C on neutrophil recruitment. Taken together, these results indicate that the activation of innate immune cells, including mast cells, macrophages, and neutrophils, is suppressed in TFM Ctreated mice but not in celecoxib treated mice. Discussion In the present study we demonstrate, using arthritis models, that TFM C, a celecoxib analogue with 205 fold lower COX 2 inhibitory activity, inhibits VEGFR Signaling Pathway autoimmune disease. TFM C differs from celecoxib by the substitution of the 4 methyl group by a trifluoromethyl group. This substitution drastically increases the IC50s for inhibition of COX1 and COX2, but does not affect the apoptotic index measured in PC3 prostate cancer cells, indicating independence between structural requirements for COX 2 inhibition and apoptosis induction. Celecoxib perturbs intracellular calcium by blocking ER Ca2 ATPases, and this activity is shared with TFM C.
In a HEK293 recombinant cell system, this Ca2 perturbation is associated with inhibition of secretion and altered intracellular interaction of IL 12 polypeptide chains with the ER chaperones calreticulin and ERp44, and results in the interception of IL 12 by HERPfollowed by degradation of the cytokine. While IC50s for inhibition of IL 12 secretion by celecoxib or TFM C are abiraterone similar, in the present paper, we show that TFM C inhibits production of various cytokines from activated macrophages and exerts a strikingly stronger inhibitory effect on arthritis models compared to celecoxib. Given that the main biological aromatase difference between celecoxib and TFM C resides in the extent of COX 1 and 2 inhibition, it is, therefore, likely that the less potent effect of TFM C on COX1/2 inactivation is a contributing, disease limiting rather than disease promoting factor in these arthritis models. Indications supporting this concept come from a study showing increased LPS induced macrophage production of TNF a by inactivation of COX 2 with celecoxib. Up regulation of TNF a by celecoxib was also reported in human PBMCs, rheumatoid synovial cultures and whole blood.
The relation between the anticipated extent of COX inhibition and production of TNF a was observed in the present study, where activated macrophages showed a tendency toward increased or decreased TNF a production in the presence of celecoxib or TFM C, respectively, compared to vehicle treated cells. In this cell system, celecoxib significantly increased production of the pro inflammatory cytokine IL 6 while TFM C suppressed it. Pending future mechanistic studies, this data indicate that prostaglandin mediated suppressive effects, or other, as yet to be identified differential TFMC/ celecoxib related effects on TNF a production may extend to other cytokines as well, and provide an important clue as to the more potent beneficial effects of TFM C compared to celecoxib in the arthritis models presented.

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