Increased caspase-3 expression and activity contribute to reduced CD3zeta expression in systemic lupus erythematosus T cells.
T cells isolated from patients with systemic lupus erythematosus (SLE) express low levels of CD3zeta-chain, a critical molecule involved in TCR-mediated signaling, but the involved mechanisms are not fully understood. In this study we examined caspase-3 as a candidate for cleaving CD3zeta in SLE T cells. We demonstrate that SLE T cells display increased expression and activity of caspase-3. Treatment of SLE T cells with the caspase-3 inhibitor Z-Asp-Glu-Val-Asp-FMK reduced proteolysis of CD3zeta and enhanced its expression. In addition, Z-Asp-Glu-Val-Asp-FMK treatment increased the association of CD3zeta with lipid rafts and simultaneously reversed the abnormal lipid raft preclustering, heightened TCR-induced calcium responses, and reduced the expression of FcRgamma-chain exclusively in SLE T cells. We conclude that caspase-3 inhibitors can normalize SLE T cell function by limiting the excessive digestion of CD3zeta-chain and suggest that such molecules can be considered in the treatment of this disease.
Krishnan
Sandeep
S
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA.
Kiang
Juliann G
JG
Fisher
Carolyn U
CU
Nambiar
Madhusoodana P
MP
Nguyen
Hang T
HT
Kyttaris
Vasileios C
VC
Chowdhury
Bhabadeb
B
Rus
Violeta
V
Tsokos
George C
GC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D003513:Cycloheximide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000276:immunology*; D008297:Male; D021962:Membrane Microdomains / Q000502:physiology; D008875:Middle Aged; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D061945:Caspase Inhibitors; D000255:Adenosine Triphosphate; D003513:Cycloheximide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002118:Calcium