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Nitric Oxide Induces Apoptosis in Spleen Lymphocytes from MRL/Ipr Mice
  1. Jim C. Oates,
  2. Gary S. Gilkeson
  1. From the Division of Rheumatology (J.C.O.), Department of Medicine, Medical University of South Carolina, Charleston, SC, and the Medical Research Service (G.S.G.), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC.
  1. Address correspondence to: Dr. Jim C. Oates, Medical University of South Carolina, Department of Medicine, Division of Rheumatology, 96 Jonathan Lucas Street, Suite 912, PO Box 250637, Charleston, SC 29425; E-mail: oatesjc{at}musc.edu.
  2. Supported by a University Research Committee grant from the Medical University of South Carolina, Office of Research and Sponsored Programs; a Career Development Award from the Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center; National Institute of Arthritis and Musculoskeletal and Skin Diseases grant numbers AR45476 and AR002193; and an Arthritis Foundation Arthritis Investigator Award.

Abstract

Background MRL/MpJ-Tnfrsf6Ipr (MRL/Ipr) mice, a murine model of systemic lupus erythematosus (SLE), have defective expression of Fas, substantially reducing signaling for apoptosis via this mechanism. However, it is known that MRL/Ipr mice have increased spontaneous apoptosis of leukocytes. These conflicting observations have stimulated interest in apoptosis in this SLE model. MRL/Ipr mice overproduce nitric oxide (NO) as autoimmune disease progresses. In vitro administration of NO may induce or decrease apoptosis depending on the cell type. Therefore, we hypothesized that NO induces MRL/Ipr spleen lymphocyte apoptosis independent of Fas receptor engagement.

Methods Percentages of apoptotic spleen lymphocytes from MRL/Ipr and BALB/cJ mice were determined ex vivo after in vivo treatment with NG-monomethyl-L-arginine (NMMA), a nitric oxide synthase (NOS) inhibitor. After culture in varying concentrations of a slow-acting NO donor, the following were determined in spleen lymphocytes: (1) levels of apoptosis, (2) the effect of phorbol myristate acid (PMA) on levels of NO-induced apoptosis, and (3) protein kinase C (PKC) activity.

Results Spleen lymphocytes from MRL/Ipr mice with active disease had increased levels of ex vivo apoptosis when compared with BALB/cJ controls. This increase was reduced by pharmacologic inhibition of NOS in MRL/Ipr but not in BALB/cJ mice. Exogenous administration of NO in vitro reduced PKC activity and induced apoptosis in MRL/Ipr spleen lymphocytes, an effect that could be reduced via coadministration of PMA in vitro.

Conclusion These results suggest that NO plays a role in spleen lymphocyte apoptosis in MRL/Ipr mice, possibly via inhibition of PKC, despite a Fas defect.

Key Words
  • apoptosis
  • lupus
  • nitric oxide

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