Karen Bedard and Karl-Heinz Krause
Karen Bedard and Karl-Heinz Krause
Karen Bedard and Karl-Heinz Krause
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278 KAREN BEDARD AND KARL-HEINZ KRAUSE<br />
identify a low ROS generating variant of p47 phox as an<br />
aggravating factor for autoimmune encephalitis (71).<br />
Thus the role of NOX autoimmune encephalitis lies in the<br />
boundary between the situation in neurodegenerative disease,<br />
where ROS are disease-causing factors <strong>and</strong> autoimmune<br />
disease where ROS appear protective.<br />
E. Endocrinology<br />
There is very strong evidence for an involvement of<br />
NOX family NADPH oxidase in thyroid function. There is<br />
also increasing evidence for their role in dysfunction of<br />
the endocrine pancreas <strong>and</strong> in the development of diabetes.<br />
In other endocrine organs, there is little evidence for<br />
a role of NOX family enzymes, albeit some immunolocalization<br />
data exist (491, 492).<br />
1. Thyroid<br />
H2O2 generation by thyrocytes was described by the<br />
early 1980s (88, 921), <strong>and</strong> an NADPH oxidase activity was<br />
quickly suggested to be the underlying mechanism (605).<br />
The discovery of the DUOX enzymes (see above) provided<br />
the molecular basis for the thyrocyte ROS generation.<br />
The physiological role of DUOX in the thyroid is well<br />
studied <strong>and</strong> well understood. Synthesis of thyroid hormones<br />
requires hydrogen peroxide for oxidation <strong>and</strong> incorporation<br />
of iodine into thyroglobulin. DUOX provides<br />
the hydrogen peroxide for this reaction. Despite the presence<br />
of a peroxidase homology domain in DUOX enzymes,<br />
the peroxidase reaction requires a separate enzyme,<br />
namely, the thyroid peroxidase. The biochemical<br />
demonstration of DUOX function is strongly supported by<br />
recent data on patients with mutations in DUOX genes<br />
(629, 690). Biallelic inactivating mutations in the DUOX2<br />
gene result in complete disruption of thyroid-hormone<br />
synthesis <strong>and</strong> are associated with severe <strong>and</strong> permanent<br />
congenital hypothyroidism, while monoallelic mutations<br />
are associated with milder, transient hypothyroidism<br />
(630). DUOX2 sequence variants associated with mild<br />
hypothyroidism have also been described (918). An unresolved<br />
issue is the question why DUOX1 cannot substitute<br />
for DUOX2 in thyroid hormone synthesis. DUOX1 is<br />
clearly expressed in the thyroid <strong>and</strong> is from a structural<br />
point of view very similar to DUOX2. Yet, DUOX2 mutations<br />
lead to a severe phenotype, while, to our knowledge,<br />
no DUOX1 mutations leading to hypothyroidism have<br />
been described.<br />
2. Endocrine pancreas<br />
At least under pathological conditions such as hyperglycemia,<br />
oxidative stress can be detected in pancreatic<br />
islet �-cells (405, 960). In contrast, islet cells appear to<br />
have a very low antioxidant capacity (318). Chronic long-<br />
Physiol Rev VOL 87 JANUARY 2007 www.prv.org<br />
term exposure to ROS has been associated with impairment<br />
of �-cell function <strong>and</strong> with complications of diabetes<br />
(305). Different sources for ROS generation by islets<br />
have been suggested; these include mitochondria <strong>and</strong>,<br />
more recently, NADPH oxidase isoforms (665, 886). Both<br />
NOX2 (protein) (648) <strong>and</strong> NOX4 (mRNA) (250) are expressed<br />
in �-cells. In both studies, an increased expression<br />
of these NOX isoforms in animal models of diabetes<br />
has been proposed (250, 648). Thus a role of ROS in the<br />
development of �-cell failure in diabetes has been widely<br />
discussed. In line with this concept are observations that<br />
glucose toxicity can be prevented by antioxidants (861).<br />
F. Gastrointestinal System <strong>and</strong> Liver<br />
1. Stomach <strong>and</strong> Helicobacter<br />
Gastric epithelium is able to generate ROS. The traditionally<br />
held view is that sources of radicals in the<br />
gastrointestinal tract include mucosal xanthine oxidase<br />
<strong>and</strong> NADPH oxidase found in the resident leukocytes of<br />
the lamina propria (670). However, more recent results<br />
suggest that NOX family NADPH oxidases might also be<br />
expressed in gastric epithelial cells. This question has<br />
been addressed predominantly in guinea pig stomach,<br />
where ROS generation by gastric mucosa has been convincingly<br />
documented (869). On the basis of several lines<br />
of evidence, NOX-type NADPH oxidases were identified<br />
as the source of this ROS generation. The responsible<br />
enzyme was initially suggested to be NOX2 based on<br />
activity <strong>and</strong> expression at the protein level (870); however,<br />
more recent results based on mRNA suggest that it<br />
is rather NOX1 (868). Helicobacter pylori lipopolysaccharide<br />
activates NOX1 <strong>and</strong> increases expression levels of<br />
NOX1 <strong>and</strong> its cytosolic subunit NOXO1 (443, 447, 870).<br />
However, the expression of NOX1 in the stomach might<br />
be species specific. In the human stomach, message for<br />
NOX2 <strong>and</strong> NOX5, but not NOX1, is found (770). In the dog<br />
stomach, Northern blot analysis suggests the expression<br />
of DUOX2 (189). In the mouse system, the expression<br />
profile of NOX enzymes in the stomach has, to our knowledge,<br />
not been studied. The underst<strong>and</strong>ing of the role<br />
played by NOX enzymes in the stomach is at a preliminary<br />
stage. In the guinea pig, NOX1 is suggested to be involved<br />
in the regulation of growth <strong>and</strong> apoptosis of gastric mucosal<br />
cells (868). In mice, the role of NOX2 in response to<br />
anti-inflammatory agents <strong>and</strong> infection has been studied.<br />
NOX2-deficient mice are less susceptible to nonsteroidal<br />
anti-inflammatory drug (NSAID) injury than wild-type<br />
mice (72), raising the possibility that NOX2 is involved in<br />
gastric injury by NSAID. Two studies have investigated<br />
gastric Helicobacter pylori infection <strong>and</strong> found markedly<br />
increased inflammation in NOX2-deficient mice (90, 450).<br />
Importantly, this was not due to a decreased host defense<br />
function, as bacterial load was either comparable (450) or<br />
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