Differential expression of factors involved in the intrinsic and extrinsic apoptotic pathways in juvenile systemic lupus erythematosus

Abstract

Dysregulated neutrophil apoptosis may result in the development of autoimmune disease by contributing to nuclear autoantigen exposure, leading to autoantibody generation and a breakdown in immune tolerance. It has previously been shown that neutrophil apoptosis is increased in juvenile-onset systemic lupus erythematosus (JSLE). This study aims to investigate the pathways involved in JSLE serum-induced apoptosis. Caspases 3, 7–9, IAP1/2, XIAP and FADD mRNA levels and TRAIL R2, BID/tBID, caspase 8 and 9 protein expression were measured in neutrophils from JSLE patients (n = 14) and controls (n = 10). The mRNA levels of caspases 7–9 were significantly higher in JSLE neutrophils than in controls, whereas the mRNA levels of IAP1, IAP2 and XIAP were decreased (p < 0.05). A decrease in neutrophil apoptosis induced by JSLE serum was observed in the presence of caspase 8 and 9 inhibitors (p < 0.05), and the activity of caspases 8 and 9 increased over time. tBID protein expression increased following incubation with JSLE serum. These data focus specifically on the expression and activity of the main caspases in the intrinsic and extrinsic apoptotic pathways. Increased expression of factors involved in the downstream signalling of the extrinsic apoptotic pathway indicates a prominent involvement of this pathway in JSLE serum-induced apoptosis.

Keywords

apoptosis caspase neutrophil systemic lupus erythematosus

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References

Steller

. Mechanisms and genes of cellular suicide. Science 1995; 267: 1445–1449.

Deveraux

Roy

Stennicke

. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998; 17: 2215–2223.

Thompson

. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267: 1456–1462.

Dallegri

Ottonello

. Tissue injury in neutrophilic inflammation. Inflamm Res 1997; 46: 382–391.

Harper

. ANCA-associated vasculitis: is there a role for neutrophil apoptosis in autoimmunity? Expert Rev Clin Immunol 2006; 2: 237–244.

Midgley

McLaren

Moots

Edwards

Beresford

. The role of neutrophil apoptosis in Juvenile Systemic Lupus Erythematosus. Arthritis Rheum 2009; 60: 2390–2401.

Igney

Krammer

. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002; 2: 277–288.

Maianski

Kuijpers

Roos

. Apoptosis of neutrophils. Acta Haematol 2004; 111: 56–66.

O’Neill

Greenan

Doyle

Fitzpatrick

Watson

. Gene profiling of in vitro and in vivo models of delayed neutrophil apoptosis: a common pathway? Biochem Soc Trans 2004; 32: 470–473.

10.

Hasegawa

Suzuki

Sakamoto

. Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: up-regulation of cIAP2 by granulocyte colony-stimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia. Blood 2003; 101: 1164–1171.

11.

Scott

Denault

Riedl

Shin

Renatus

Salvesen

. XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs. EMBO J 2005; 24: 645–655.

12.

Hochberg

. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725–1725.

13.

Whyte

Savill

Meagher

Lee

Haslett

. Coupling of neutrophil apoptosis to recognition by macrophages: coordinated acceleration by protein synthesis inhibitors. J Leukoc Biol 1997; 62: 195–202.

14.

Isenberg

Rahman

Allen

. BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group’s disease activity index for patients with systemic lupus erythematosus. Rheumatology (Oxford) 2005; 44: 902–906.

15.

Bengtsson

Sturfelt

Gullstrand

Truedsson

. Induction of apoptosis in monocytes and lymphocytes by serum from patients with systemic lupus erythematosus - an additional mechanism to increased autoantigen load? Clin Exp Immunol 2004; 135: 535–543.

16.

Courtney

Crockard

Williamson

Irvine

Kennedy

Bell

. Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: relations with disease activity, antibodies to double stranded DNA, and neutropenia. Ann Rheum Dis 1999; 58: 309–314.

17.

Bijl

Limburg

Kallenberg

. New insights into the pathogenesis of systemic lupus erythematosus (SLE): the role of apoptosis. Neth J Med 2001; 59: 66–75.

18.

Srinivasula

Ashwell

. IAPs: what’s in a name? Mol Cell 2008; 30: 123–135.

19.

Yang

. The IAP family: endogenous caspase inhibitors with multiple biological activities. Cell Res 2000; 10: 169–177.

20.

Eckelman

Salvesen

Scott

. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 2006; 7: 988–994.

21.

Krishnan

Kiang

Fisher

. Increased caspase-3 expression and activity contribute to reduced CD3zeta expression in systemic lupus erythematosus T cells. J Immunol 2005; 175: 3417–3423.

22.

Thornberry

Rano

Peterson

. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem 1997; 272: 17907–17911.

23.

Walsh

Cullen

Sheridan

Luthi

Gerner

Martin

. Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proc Natl Acad Sci U S A 2008; 105: 12815–12819.

24.

Schultz

Harrington

Jr . Apoptosis: programmed cell death at a molecular level. Semin Arthritis Rheum 2003; 32: 345–369.

25.

Zhu

Yuan

. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94: 491–501.

26.

Bengtsson

Gullstrand

Truedsson

Sturfelt

. SLE serum induces classical caspase-dependent apoptosis independent of death receptors. Clin Immunol 2008; 126: 57–66.