Reactive oxygen species (ROS) are a heterogeneous group of highly reactive molecules that oxidize targets in a biologic system. During steady-state conditions, ROS are constantly produced in the electron-transport chain during cellular respiration and by various constitutively active oxidases. ROS production can also be induced by activation of the phagocyte NADPH oxidase 2 (NOX2) complex in a process generally referred to as an oxidative burst. The induced ROS have long been considered proinflammatory, causing cell and tissue destruction. Recent findings have challenged this inflammatory role of ROS, and today, ROS are also known to regulate immune responses and cell proliferation and to determine T-cell autoreactivity. NOX2-derived ROS have been shown to suppress antigen-dependent T-cell reactivity and remarkably to reduce the severity of experimental arthritis in both rats and mice. In this review, we discuss the role of ROS and the NOX2 complex as suppressors of autoimmunity, inflammation, and arthritis.

We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.

The current review on the function of neutrophil cytosolic factor 1 (NCF1) and induced reactive oxygen species (ROS) is based on a genetic search for the major genes controlling autoimmune inflammatory disorders. Surprisingly, the disease-promoting allele determined a lower ROS response and was therefore in complete contrast to the prevailing dogma. Once cloned, it opened the possibility to dissect this complex field from a new angle and with the possibilities to study the role of ROS in vivo. We found that NCF1 and NADPH oxidase 2 (NOX2) complex-derived ROS is an important regulator of several chronic inflammatory disorders by using models for rheumatoid arthritis, multiple sclerosis, psoriasis and psoriasis arthritis, gout, and lupus. ROS could therefore affect many different types of diseases and the common denominator seems to be that ROS regulate macrophages, which prevents inflammation from going chronic. The role of ROS is currently changing from being seen as toxic agents that will promote inflammation toward a more complex view with ROS as crucial regulators of immune and inflammatory pathways.

1 Proinflammatory cytokines and bacterial products trigger inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in inflammatory and tissue cells. In inflammation, NO acts as an important mediator having both proinflammatory and destructive effects. 2 Protein kinase C (PKC) is a family of serine-threonine protein kinase isoenzymes involved in signal transduction pathways related to inflammatory responses. The aim of the present study was to investigate the role of classical PKC (cPKC) isoenzymes in the regulation of iNOS expression and NO production in murine J774 macrophages and the mechanisms involved. 3 RO318220 (inhibits PKCb, PKCg and PKCe), GÖ 6976 (inhibits cPKC isoenzymes PKCa and PKCb) and LY333531 (inhibits PKCb) reduced lipopolysaccharide (LPS)-induced NO production and iNOS expression in a dose-dependent manner as did 6 h pretreatment with 1 mM phorbol 12-myristate 13-acetate (PMA) (which was shown to downregulate PKC expression). 4 PKC inhibitors also reduced LPS-induced iNOS mRNA levels, but they did not affect the half-life of iNOS mRNA. PKC inhibitors did not alter LPS-induced activation of NF-kB as measured by electrophoretic mobility shift assay. 5 All PKC inhibitors used and pretreatment with 1 mM PMA inhibited signal transducer and activator of transcription 1 (STAT1) activation as measured by the translocation of STAT1a from the cytosol to the nucleus by Western blot. In addition, inhibition of STAT1 activation by AG-490, an inhibitor of JAK-2, also reduced NO production. 6 These results suggest that cPKC isoenzymes, especially PKCb, mediate the upregulation of iNOS expression and NO production in activated macrophages in an NF-kB-independent manner, possibly through the activation of transcription factor STAT1.