Signaling abnormalities in systemic lupus erythematosus as potential drug targets.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by T-cell, B-cell, and dendritic cell dysfunction and antinuclear autoantibody production. Much of the knowledge that has been gained about SLE in recent years is related to molecular signaling abnormalities present in the disease. Signaling through the T-cell receptor (TCR) is affected in SLE by alterations in the localization, amount, and activity of numerous protein kinases. TCR stimulation releases calcium from intracellular stores, which triggers an influx of extracellular calcium and activates the transcription of many genes, including interleukin-2. Short-term calcium fluxing is exaggerated in SLE, but long-term calcium fluxing is diminished and may account for sub-optimal interleukin-2 production. SLE T-cells have persistently hyperpolarized mitochondria associated with increased mitochondrial mass, high levels of reactive oxygen species (ROS) and low levels of ATP, which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus stimulating inflammation in SLE. The pentose phosphate pathway impacts the mitochondrial potential and represents a target for possible intervention. Nitric oxide (NO) is a potential link to tie together the signaling and mitochondrial abnormalities in SLE. NO-induced mitochondrial biogenesis recapitulates the TCR-stimulated calcium fluxing abnormalities of SLE T-cells. Since mitochondria can store calcium, the increase in mitochondrial mass may be implicated in the aberrant calcium fluxing in SLE T cells. The mammalian target of rapamycin senses the mitochondrial potential and regulates calcium release, serving as a novel target of treatment of SLE.

• Authors: David Fernandez, Eduardo Bonilla, Paul Phillips, Andras Perl
• Journal: Endocrine, metabolic & immune disorders drug targets (Endocr Metab Immune Disord Drug Targets) Vol. 6 Issue 4 Pg. 305-11 (Dec 2006) ISSN: 1871-5303 [Print] United Arab Emirates
• PMID: 17214576 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• CREM protein, human
• Interleukin-2
• Reactive Oxygen Species
• Receptors, Antigen, T-Cell
• Cyclic AMP Response Element Modulator
• Nitric Oxide
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (physiology)
• Animals
• Calcium Signaling (drug effects, physiology)
• Cyclic AMP Response Element Modulator (physiology)
• Humans
• Interleukin-2 (physiology)
• Lupus Erythematosus, Systemic (drug therapy, physiopathology)
• Mitochondria (physiology)
• Nitric Oxide (physiology)
• Reactive Oxygen Species (metabolism)
• Receptors, Antigen, T-Cell (drug effects, physiology)
• Signal Transduction (drug effects, physiology)