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Increased Expression of Arginase II in Patients with Different Forms of Arthritis. Implications of the Regulation of Nitric Oxide

INES CORRALIZA and SALVADOR MONCADA

ABSTRACT.

Objective. To investigate the expression of arginase isoforms in patients with different forms of arthritis and the possible implications of the synthesis of nitric oxide (NO).

Methods. Arginase activity was measured in synovial fluid (SF) cells from patients with different forms of arthritis, either directly or after in vitro stimulation with cytokines. The identity of the isoform expressed was confirmed by reverse transcription polymerase chain reaction. We measured both arginase activity and NO production in SF macrophages and synovial membrane fibroblasts from patients with rheumatoid arthritis (RA).

Results. Arginase II was the isoform expressed in SF cells. In SF macrophages, dibutyryl-cAMP (dBt-cAMP), prostaglandin E₂ (PGE₂), and lipopolysaccharide (LPS) further increased the enzyme activity, while NO production was not detected even in the presence of Th1-like cytokines. In contrast, synovial membrane fibroblasts from patients with RA released NO into the culture media. Moreover, dBt-cAMP, PGE₂, and transforming growth factor-ß, which induced arginase II, reduced the levels of NO. Reciprocally, the induction of NO by Th1 cytokines inhibited arginase activity levels.

Conclusion. Arginase II expression is upregulated in RA and may increase cell proliferation by providing L-ornithine, which is the substrate of polyamine biosynthesis. In cells where both arginase II and inducible NO synthase activity occurs, there is a reciprocal regulation, suggesting that agents that induce arginase II in synovial cells could downregulate the levels of NO and divert L-arginine metabolism toward cell proliferation and/or tissue regeneration. (J Rheumatol 2002;29:2261-5)

Key Indexing Terms:

ARGINASE II
INDUCIBLE NITRIC OXIDE SYNTHASE
ARTHRITIS
CYTOKINES

From the Wolfson Institute for Biomedical Research, University College London, London, UK.
Dr. Corraliza was the recipient of a Spanish post-doctoral grant from the Ministry of Education and Science.
I. Corraliza, PhD, Assistant Professor; S. Moncada, PhD, MD.
Address reprint requests to Dr. I. Corraliza, Department of Biochemistry and Molecular Biology, Veterinary Faculty, University of Extremadura, Avda de la Universidad S/N, 10071 Caceres, Spain. E-mail: corragen@unex.es

Submitted September 4, 2001; revision accepted May 5, 2002.