Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator?

Kolb, Hubert; Kolb-Bachofen, Victoria

doi:10.1016/s0167-5699(98)01366-8

Cited by 237 publications

(152 citation statements)

References 72 publications

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“…Indeed, some studies of NOS2 inhibition in experimental autoimmune diseases reported no amelioration or even an exarcebation of the autoaggression. 6 Accordingly, it has been recently suggested that NO is not just a cytotoxic molecule but also an important regulator of the Th1/Th2 balance limiting the Th1 response, 6 which is consistent with the observation that mice with a disrupted NOS2 gene exhibit enhanced Th1 reactivity. 18 Although single alleles have been formerly associated to disease predisposition in several disorders, 10,19 we analysed the possible effect of category alleles defined by length on RA predisposition, specially given the fact that functional studies have reported that medium repeat alleles might be associated to high NO production.…”

Section: Resultssupporting

confidence: 59%

“…3 Likewise, it has been shown that peripheral blood mononuclear cells (PBMC) from RA patients, have increased NOS2 expression and enhanced formation of NO that correlates with disease activity 4 and similarly, NO has been shown as a key mediator of apoptosis within the RA joints 5 as well as an important regulator of the Th1/Th2 balance in autoinmune diseases. 6 The final piece of evidence comes from the finding that administration of NOS2 inhibitors has provided beneficial effects on animal models of RA. 3 On this basis we considered the human NOS2 gene as a novel candidate for genetic association with RA susceptibility and severity.…”

Section: Introductionmentioning

confidence: 99%

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Genetic determinants of rheumatoid arthritis: the inducible nitric oxide synthase (NOS2) gene promoter polymorphism

et al. 2002

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Section: Resultssupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Genetic determinants of rheumatoid arthritis: the inducible nitric oxide synthase (NOS2) gene promoter polymorphism

et al. 2002

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“…Importantly, Dixit and Parvizi [28] reported significantly high secretion of adrenocorticotropin (ACTH) and nitric oxide (NO) from peripheral blood lymphocytes on day 7 of pregnancy compared with that in cyclic cows. In addition, both ACTH and NO cause a shift toward Th2 by increasing the levels of Th2 cytokines and decreasing the levels of Th1 cytokines [29,30].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Interferon-stimulated Genes and Interleukin-10 in Peripheral Blood Immune Cells During Early Pregnancy in Dairy Cows

et al. 2012

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Abstract. In cows, interferon-tau (IFNT) regulates maternal recognition around days 15-19 after artificial insemination (AI). The present study hypothesized that if key target genes of IFNT are clearly upregulated in earlier stages of pregnancy, these genes could be use as indices of future pregnancy in cows. Therefore, we determined the expression of these genes in peripheral blood mononuclear leukocytes (PBMCs) and polymorphonuclear granulocytes (PMNs) during the maternal recognition period (MRP). Twenty multiparous Holstein cows were subjected to AI on day 0 and categorized into the following groups: pregnancy (Preg, n = 9), embryonic death (ED, n = 5) and non-pregnancy (NP, n = 6). Progesterone levels in the Preg group were higher than those in the NP group on days 12-21. ISG15 and OAS-1 (IFN-stimulated genes: ISGs) mRNA in PBMCs on day 8 was higher in the Preg group than in the NP group, and these mRNAs in PMNs was higher in the Preg group on day 5 than in the NP and ED groups. Interleukin-10 (IL-10, Th2 cytokine) mRNA expression increased on day 8 in the PBMCs of pregnant cows. Tumor necrosis factor α (TNFα, Th1 cytokine) mRNA expression was stable in all groups. In an in vitro cell culture experiment, IFNT stimulated mRNA expression of ISGs in both PBMCs and PMNs. IFNT stimulated IL-10 mRNA expression in PBMCs, whereas IFNT increased TNFα mRNA levels in PBMCs in vitro. The results suggest that ISGs and IL-10 could be responsive to IFNT before the MRP in peripheral blood immune cells and may be useful target genes for reliable indices of pregnancy before the MRP. Key words: Cow, Immune cells, Interferon tau, Pregnancy (J. Reprod. Dev. 58: [84][85][86][87][88][89][90] 2012) D uring the past 5 decades, milk production per cow has dramatically increased because of improved management, nutrition, and genetic selection [1,2]. In contrast, the decreases in fertility and conception rates of the modern high-producing dairy cow are the major causes of economic loss for dairy producers [2,3]. After establishment of pregnancy in domestic ruminants, the conceptus secretes interferon-tau (IFNT) as a maternal recognition factor [4]. IFNT acts in the uterus around day 16 after insemination and prevents luteolysis by inhibiting prostaglandin F 2α release, resulting in the maintenance of corpus luteum function; therefore, this period is termed the maternal recognition period (MRP) [5]. IFNT induces the synthesis and secretion of IFN-stimulated genes (ISGs) such as ISG15, 2′,5′-oligoadenylate synthetase (OAS-1), IFN regulatory factor 1, Mx1 and Mx2 not only in the uterus but also in blood cells in ewes and cows [6][7][8][9][10]. In fact, in bovine peripheral blood leukocytes, ISG15 mRNA levels were higher in pregnant cows than in nonpregnant cows on days 18 and 20 after artificial insemination (AI) [7][8][9]. Technology for the early detection of pregnancy is needed to identify nonpregnant cows and to synchronize and artificially inseminate these cows prior to the next ovulation, and many studies have focused on identify...

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“…Less is known about a role for NOS2/NO in the generation and regulation of adaptive immune responses, in particular adaptive response of an autoimmune nature. Because infection is often associated with autoimmune diseases in humans, and bacterial adjuvant is required to induce experimental autoimmune diseases in rodents (3,4), innate immunity with NO involvement has been suggested to participate in the development of such diseases (5). The contributions of NOS2/NO in autoimmune disease have been investigated by pharmacological and genetic blockade of NOS2, although these approaches have yielded contrasting results in some experimental systems (reviewed in Ref.…”

Section: Control Of the Autoimmune Response By Type 2 Nitric Oxide Symentioning

confidence: 99%

“…The contributions of NOS2/NO in autoimmune disease have been investigated by pharmacological and genetic blockade of NOS2, although these approaches have yielded contrasting results in some experimental systems (reviewed in Ref. 5). Nevertheless, these studies have suggested that NOS2/NO may play a dual role as cytotoxic or regulatory molecule in some T cell-mediated experimental models of autoimmune disease, including diabetes (reviewed in Ref.…”

Section: Control Of the Autoimmune Response By Type 2 Nitric Oxide Symentioning

confidence: 99%

Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase

Shi

Flodström

Kim

et al. 2001

The Journal of Immunology

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Immune defense against pathogens often requires NO, synthesized by type 2 NO synthase (NOS2). To discern whether this axis could participate in an autoimmune response, we immunized NOS2-deficient mice with the autoantigen acetylcholine receptor, inducing muscle weakness characteristic of myasthenia gravis, a T cell-dependent Ab-mediated autoimmune disease. We found that the acetylcholine receptor-immunized NOS2-deficient mice developed an exacerbated form of myasthenia gravis, and demonstrated that NOS2 expression limits autoreactive T cell determinant spreading and diversification of the autoantibody repertoire, a process driven by macrophages. Thus, NOS2/NO is important for silencing autoreactive T cells and may restrict bystander autoimmune reactions following the innate immune response.

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Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator?

Cited by 237 publications

References 72 publications

Genetic determinants of rheumatoid arthritis: the inducible nitric oxide synthase (NOS2) gene promoter polymorphism

Genetic determinants of rheumatoid arthritis: the inducible nitric oxide synthase (NOS2) gene promoter polymorphism

Upregulation of Interferon-stimulated Genes and Interleukin-10 in Peripheral Blood Immune Cells During Early Pregnancy in Dairy Cows

Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase

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