Nitric oxide: Cytokine-regulation of nitric oxide in host resistance to intracellular pathogens

Green, Shawn J.; Scheller, Libia F.; Marletta, Michael A.; Seguin, M C; Klotz, F.; Slayter, M V; Nelson, Barbara J.; Nacy, Carol A.

doi:10.1016/0165-2478(94)00158-8

Cited by 209 publications

(147 citation statements)

References 37 publications

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“…Because we found that LPS and IFN-␥ led to a decrease in TfR mRNA levels and to an increase in ferritin synthesis, oxidative stress is unlikely to be involved in the above responses. Moreover, the H 2 O 2 activates IRP-1 without affecting IRP-2 (57), 2 whereas we observed that LPS/IFN-␥ treatment increased IRP-1 activity and dramatically decreased IRP-2 binding, changes that could be prevented by specific iNOS inhibitors (Fig. 2).…”

Section: Lps/ifn-␥-treated Raw 2647 Cellsmentioning

confidence: 83%

“…It is now well established that cytostatic and cytotoxic effects of murine macrophages are caused in part by nitric oxide (NO) produced enzymatically by the stepwise oxidation of L-arginine to NO and L-citrulline (2,3). The cytotoxic function of NO requires that it is produced in relatively large quantities in macrophages and some other cells and this is accomplished by inducible NO synthase (iNOS) (3).…”

mentioning

confidence: 99%

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Effects of Interferon-γ and Lipopolysaccharide on Macrophage Iron Metabolism Are Mediated by Nitric Oxide-induced Degradation of Iron Regulatory Protein 2

Kim

Ponka

2000

Journal of Biological Chemistry

138

113

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Iron regulatory proteins (IRP-1 and IRP-2) control the synthesis of transferrin receptors (TfR) and ferritin by binding to iron-responsive elements, which are located in the 3-untranslated region and the 5-untranslated region of their respective mRNAs. Cellular iron levels affect binding of IRPs to iron-responsive elements and consequently expression of TfR and ferritin. Moreover, NO ⅐ , a redox species of nitric oxide that interacts primarily with iron, can activate IRP-1 RNA binding activity resulting in an increase in TfR mRNA levels. Recently we found that treatment of RAW 264.7 cells (a murine macrophage cell line) with NO ؉ (nitrosonium ion, which causes S-nitrosylation of thiol groups) resulted in a rapid decrease in RNA binding of IRP-2 followed by IRP-2 degradation, and these changes were associated with a decrease in TfR mRNA levels (Kim, S., and Ponka, P. Macrophages stimulated by cytokines, such as interferon-␥ (IFN-␥), 1 or microbial components, such as lipopolysaccharide (LPS), take part in the nonspecific resistance against pathogens (1). It is now well established that cytostatic and cytotoxic effects of murine macrophages are caused in part by nitric oxide (NO) produced enzymatically by the stepwise oxidation of L-arginine to NO and L-citrulline (2, 3). The cytotoxic function of NO requires that it is produced in relatively large quantities in macrophages and some other cells and this is accomplished by inducible NO synthase (iNOS) (3). Many of the cytotoxic effects of NO can be explained by its reactivity with iron in the active sites of critically important molecules such as mitochondrial aconitase, ribonucleotide reductase, and the [Fe-S] proteins of the mitochondrial respiratory system (reviewed in Refs. 3 and 4). Moreover, the identification of the [4Fe-4S] cluster of mitochondrial aconitase as a target susceptible to inactivation by NO suggested that NO may also be involved in the regulation of iron regulatory protein (IRP)-1, which is closely related to mitochondrial aconitase (5-7). Although many actions of NO are mediated by its binding to either non-heme or heme iron (8), this metal is not the only target for NO. The oxidized form of NO, the nitrosonium ion (NO ϩ ), can S-nitrosylate proteins via their thiol groups, a modification that may have important regulatory functions (9 -14).IRP-1 and IRP-2 are cytoplasmic proteins known to interact with specific nucleotide sequences, known as iron-responsive elements (IREs) (reviewed in Refs. 15-19), which are located in the 5Ј-untranslated region of ferritin mRNA (20) and the 3Ј-untranslated region of transferrin receptor (TfR) mRNA (21). The interactions of IRPs with IREs control cellular iron metabolism in the following manner: When cellular iron becomes limiting, IRP-2 is present in the cytosol, and the IRP-1 is recruited into the high affinity binding state. The binding of IRPs to the IRE in the 5Ј-untranslated region of the ferritin mRNA blocks the translation of ferritin, whereas an association of IRPs with IREs in the 3Ј-untranslated r...

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Section: Lps/ifn-␥-treated Raw 2647 Cellsmentioning

confidence: 83%

mentioning

confidence: 99%

Effects of Interferon-γ and Lipopolysaccharide on Macrophage Iron Metabolism Are Mediated by Nitric Oxide-induced Degradation of Iron Regulatory Protein 2

Kim

Ponka

2000

Journal of Biological Chemistry

138

113

View full text Add to dashboard Cite

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“…The activation of the NF-κB-dependent iNOS promoter supports the inf lammation-mediated stimulation of iNOS transcription (30). Furthermore, iNOS produces large quantities of NO following stimulation by IL-1 and TNF-α (31).…”

Section: Discussionmentioning

confidence: 99%

N‑methyl pyrrolidone promotes ankle fracture healing by inhibiting inflammation via suppression of the mitogen‑activated protein kinase signaling pathway

et al. 2018

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Abstract. N-methyl pyrrolidone (NMP), a small bioactive molecule, has the potential to stimulate bone formation and inhibit osteoclast differentiation. The aim of the present study was to investigate the effect of NMP on the inflammatory response and underlying molecular mechanisms in MG-63 cells. The mRNA and protein expression of cytokines from peripheral blood in children with or without ankle fracture were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA, respectively. MG-63 cells were pre-treated with/without NMP and stimulated with 1 µM bradykinin (BK). The production of cytokines from MG-63 cells was assessed by western blotting and RT-qPCR. The expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein were measured using western blotting and/or RT-qPCR. Western blotting was used to examine the activation level of mitogen activated protein kinase. Compared with healthy children, levels of tumor necrosis factor (TNF-α), interleukin (IL)-1β and IL-6 mRNA and protein were upregulated in children with ankle fracture. NMP treatment did not induce cytotoxicity in MG-63 cells. The BK-induced upregulation of TNF-α, IL-1β, IL-6, iNOS and COX-2 mRNA and protein was reversed in a dose-dependent manner by NMP. Furthermore, NMP downregulated the activation of c-Jun NH2-terminal kinase and p38 pathways, but not the extracellular signal-related kinase pathway. Therefore, the results of the current study demonstrate that NMP inhibits inflammation dependent on the mitogen-activated protein kinase pathway in MG-63 cells, indicating that it may be beneficial in the healing of fractures.

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“…effector molecules following their activation by IFN-γ and TNF [17,18]. Therefore, we assessed whether the susceptibility to L. major in PIP KO mice was primarily related to the impaired Th1-cell (IFN-γ) response or is multifactorial, that is, also related to defective macrophage function.…”

Section: Impaired No Production and Parasite Kill In Macrophages Frommentioning

confidence: 99%

Deficiency of prolactin‐inducible protein leads to impaired Th1 immune response and susceptibility to Leishmania major in mice

Liu

Mou

et al. 2015

Eur J Immunol

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Although the strategic production of prolactin-inducible protein (PIP) at several ports of pathogen entry into the body suggests it might play a role in host defense, no study has directly implicated it in immunity against any infectious agent. Here, we show for the first time that PIP deficiency is associated with reduced numbers of CD4 + T cells in peripheral lymphoid tissues and impaired CD4 + Th1-cell differentiation in vitro. In vivo, CD4+ T cells from OVA-immunized, PIP-deficient mice showed significantly impaired proliferation and IFN-γ production following in vitro restimulation. Furthermore, PIPdeficient mice were highly susceptible to Leishmani major infection and failed to control lesion progression and parasite proliferation. This susceptibility was associated with impaired NO production and leishmanicidal activity of PIP KO macrophages following IFN-γ and LPS stimulation. Collectively, our findings implicate PIP as an important regulator of CD4 + Th1-cell-mediated immunity. Keywords: IFN-γ r Leishmania r Macrophages r Protozoan r Th1 cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe mouse prolactin-inducible protein (PIP), also known as the mouse submaxillary gland protein, is a 14 kDa protein present in the saliva of mice. The function of PIP is not known, but it is suspected to play a role in host defense against pathogens [1][2][3][4][5][6] because it is expressed in tissues strategically located at several Correspondence: Dr. Jude E. Uzonna e-mail: jude.uzonna@med.umanitoba.ca ports of pathogen entry, including the skin, eyes, and mouth [7]. Although a definitive evidence showing a role for PIP in host immunity is lacking, its ability to potentially bind with several important host molecules including CD4 + T-cell receptor, IgG, actin, zinc α2-glycoprotein, fibronectin, and enamel pellicle suggests it may have important biological functions [8][9][10][11][12][13]. Indeed, it has been shown that PIP is a ligand of the CD4 molecule and a potent inhibitor of * These authors contributed equally to this manuscript.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1082-1091 Immunity to infection 1083 T-cell apoptosis induced by sequential CD4/T-cell receptor triggering, which in part modulates the immune response during viral infection by interfering with the functions mediated by the CD4 molecule [5,6,14]. Furthermore, PIP has been reported to exhibit a mitogenic effect for both normal and malignant breast epithelial cells [15], strongly suggesting that it might play a critical role in differentiation, proliferation, and function of immune cells.Our previous studies show that PIP KO mice have enlarged submandibular lymph nodes and thymic medulla [16]. However, to date, no studies have addressed the contributions of PIP in T-cell responses to either model Ags or infectious agents. Our major aim in the present study is to investigate whether PIP has immunoregulatory function...

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Nitric oxide: Cytokine-regulation of nitric oxide in host resistance to intracellular pathogens

Cited by 209 publications

References 37 publications

Effects of Interferon-γ and Lipopolysaccharide on Macrophage Iron Metabolism Are Mediated by Nitric Oxide-induced Degradation of Iron Regulatory Protein 2

Effects of Interferon-γ and Lipopolysaccharide on Macrophage Iron Metabolism Are Mediated by Nitric Oxide-induced Degradation of Iron Regulatory Protein 2

N‑methyl pyrrolidone promotes ankle fracture healing by inhibiting inflammation via suppression of the mitogen‑activated protein kinase signaling pathway

Deficiency of prolactin‐inducible protein leads to impaired Th1 immune response and susceptibility to Leishmania major in mice

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