Autoreactive lupus T cells use COX-2 to escape death, can be eliminated by some coxibs

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Apr 15, 2004

Autoreactive lupus T cells use COX-2 to escape death, can be eliminated by

some coxibs

Chicago, IL - The autoreactive T cells that drive production of pathogenic

autoantibodies in systemic lupus erythematosus (SLE) escape inactivation and

apoptosis in part by upregulating cyclooxygenase-2 (COX-2). Groundbreaking

work by Dr Syamal K Datta and colleagues, reported in the April 2004 issue

of Nature Medicine, shows that these activated T cells can be eliminated by

apoptosis after treatment with some COX-2 inhibitors and that this result is

due to something other than the drugs' effect on COX-2 enzymatic activity

[1].

" Our results point to a new mechanism that will change the way people think

about COX-2-inhibitor therapy. "

" Our results point to a new mechanism that will change the way people think

about COX-2-inhibitor therapy, " Datta tells rheumawire. " Our studies also

have implications for treatment of other diseases with better designed COX-2

inhibitors. "

Some COX-2 inhibitors cause apoptosis of lupus T cells

Datta et al used gene-microarray profiling and extensive biochemical and

functional studies to uncover the novel pathway by which autoimmune lupus T

cells resist programmed cell death. The death-resistance pathway involves

COX-2 and the antiapoptotic molecule cFLIP. " Until now, the mechanism that

maintains the lupus T cells that drive the production of pathogenic

autoantibodies was unknown, " Datta says.The most important points in this

study were that autoimmune T-helper cells in SLE resist anergy and apoptosis

by upregulating COX-2 expression, that this effect appears to be separate

from the COX-2 enzymatic effects, and that somebut not allCOX-2 inhibitors

can reverse the effect, cause apoptosis of lupus T cells, and suppress

production of pathogenic autoantibodies.

" Using COX-2-specific inhibitors, we found that we could cause death of the

autoimmune T cells and block lupus autoimmunity. Most unexpectedly, only

some COX-2 inhibitors have this beneficial effect, which may depend on their

structural peculiarity, and not because they inhibit the enzymatic function

of COX-2, such as increased production of prostaglandin (PGE2), " Datta says.

Treatment with the COX-2 inhibitors celecoxib, niflumic acid, and SC58125

induced apoptosis of the activated lupus T cells, but treatment with

indomethacin, rofecoxib, or NS398 did not.

Transcription of COX-2 gene upregulated in lupus

Datta et all examined gene expression patterns under anergy-inducing and

activation-induced cell death (AICD) conditions in CD4+ T cells from lupus

patients and from normal subjects. They found 591 genes differentially

expressed in T cells of lupus patients. Cluster analysis identified a

COX-2-encoding gene in the SLE-favored cluster. Transcription of this gene

was increased in 8 of 9 lupus patients. COX-2 mRNA expression was

significantly higher and prolonged in the lupus T cells.

Anergy-inducing treatment of the T cells was followed by sustained

upregulation of COX-2 in the lupus T cells, but by only transient and modest

upregulation of COX-2 in T cells from normal subjects.

The apoptosis of human lupus T cell induced by celecoxib, niflumic acid, or

SC58125 was mediated by increased expression of Fas and Fas-ligand. cFLIP

prevents Fas-mediated apoptosis by inhibiting various signaling molecules,

and treatment with celecoxib or niflumic acid decreased cFLIP levels and

increased permeabilization of mitochondrial membrane.

A radical change in COX-2-inhibitor therapy?

" Our studies pave the way for the design of better COX-2 inhibitors or other

molecules that interfere with the lupus T cell's death-resistance pathway, "

says Datta, who also points out that the nuclear localization of COX-2

suggests a role in transcriptional regulation that is independent of PGE2.

" COX-2 inhibitors have been given to lupus patients in doses that are much

lower than the concentration required to achieve apoptosis. In those

studies, the COX-2 inhibitors were tried with the concept that they would

inhibit COX-2 enzymatic activity and prostaglandin or thromboxane

production, thus reducing activation of inflammatory cells such as

macrophages or mesangial cells in the glomeruli of the lupus kidney, or that

they would relieve pain like nonsteroidal anti-inflammatory drugs. They were

given in doses too low to achieve elimination of autoimmune T cells, " Datta

says. " Our results should bring about a radical change in COX-2-inhibitor

therapy design, as far as dosage and type of inhibitor to be used, because

the target and goal for the therapy would be different. For instance,

high-dose pulse therapy might be tried rather than low-dose chronic therapy,

which does have toxic effects in the kidney. "

Janis

Source

1. Xu L, Zhang L, Yi Y, Kang HK, Datta SK. Human lupus T cells resist

inactivation and escape death by upregulating COX-2. Nat Med 2004 Apr;

10(4):411-5. .