Extrahepatic expression of plasma protein genes during inflammation

Kalmovarin, Nuanthip; Friedrichs, William E.; O'brien, Houston V.; Linehan, Leslie A.; Bowman, Barbara H.; Yang, Funmei

doi:10.1007/bf00917353

Cited by 90 publications

(69 citation statements)

References 30 publications

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“…We understand even less about the function of macrophage production of Cp. Its induction by IFN-␥ (and by endotoxin [12]) suggests a role in host defense, a possibility consistent with previous observations (16,35). Our own finding that Cp has a potent prooxidant activity is also consistent with a microbicidal function (25,26).…”

Section: Discussionsupporting

confidence: 80%

Transcript-Selective Translational Silencing by Gamma Interferon Is Directed by a Novel Structural Element in the Ceruloplasmin mRNA 3′ Untranslated Region

Sampath

Mazumder

Seshadri

et al. 2003

Molecular and Cellular Biology

114

118

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Transcript-selective translational control of eukaryotic gene expression is often directed by a structural element in the 3 untranslated region (3-UTR) of the mRNA. In the case of ceruloplasmin (Cp), induced synthesis of the protein by gamma interferon (IFN-␥) in U937 monocytic cells is halted by a delayed translational silencing mechanism requiring the binding of a cytosolic inhibitor to the Cp 3-UTR. Silencing requires the essential elements of mRNA circularization, i.e., eukaryotic initiation factor 4G, poly(A)-binding protein, and poly(A) tail. We here determined the minimal silencing element in the Cp 3-UTR by progressive deletions from both termini. A minimal, 29-nucleotide (nt) element was determined by gel shift assay to be sufficient for maximal binding of the IFN-␥-activated inhibitor of translation (GAIT), an as-yet-unidentified protein or complex. The interaction was shown to be functional by an in vitro translation assay in which the GAIT element was used as a decoy to overcome translational silencing. Mutation analysis showed that the GAIT element contained a 5-nt terminal loop, a weak 3-bp helix, an asymmetric internal bulge, and a proximal 6-bp helical stem. Two invariant loop residues essential for binding activity were identified. Ligation of the GAIT element immediately downstream of a luciferase reporter conferred the translational silencing response to the heterologous transcript in vitro and in vivo; a construct containing a nonbinding, mutated GAIT element was ineffective. Translational silencing of Cp, and possibly other transcripts, mediated by the GAIT element may contribute to the resolution of the local inflammatory response following cytokine activation of macrophages.

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Section: Discussionsupporting

confidence: 80%

Transcript-Selective Translational Silencing by Gamma Interferon Is Directed by a Novel Structural Element in the Ceruloplasmin mRNA 3′ Untranslated Region

Sampath

Mazumder

Seshadri

et al. 2003

Molecular and Cellular Biology

114

118

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“…[29][30][31] Circulating amounts of Hp (0.45-3 mg/mL in normal human serum) are well known to increase during the acute phase response because of an enhanced rate of synthesis in response to inflammatory cytokines, such as interleukin-6 (IL-6) and IL-1. 32,33 Hp is therefore also a clinical marker of the acute phase response (high Hp levels) besides being a routine clinical marker of intravascular hemolysis (low Hp levels).…”

Section: Expression and Presence In Plasmamentioning

confidence: 99%

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Nielsen

Moestrup

2009

Blood

135

109

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Haptoglobin, the haptoglobin-hemoglobin receptor CD163, and the heme oxygenase-1 are proteins with a well-established function in the clearance and metabolism of "free" hemoglobin released during intravascular hemolysis. This scavenging system counteracts the potentially harmful oxidative and NO-scavenging effects associated with "free" hemoglobin, and, furthermore, elicits an anti-inflammatory response. In the late primate evolution, haptoglobin variants with distinct functions have arisen, including haptoglobin polymers and the haptoglobin-related protein. The latter associates with a subspecies of high-density lipoprotein (HDL) particles playing a crucial role in the innate immunity against certain trypanosome parasites. Recent studies have elucidated this fairly sophisticated immune defense mechanism that takes advantage of a trypanosomal haptoglobin-hemoglobin receptor evolved to supply the parasite with heme. Because of the high resemblance between haptoglobin and haptoglobinrelated protein, the receptor also takes up the complex of hemoglobin and the HDL- IntroductionHaptoglobin (Hp), an abundant acute phase plasma glycoprotein of the ␣ 2 -globulin fraction, was initially reported in 1938 by Polonovski and Jayle to be a "plasma substance" that binds hemoglobin (Hb). 1 In agreement with this initial characterization and its designation as "haptoglobin" (Greek: haptein, "to bind" ϩ [hemo]globin), Hp has a well-established role in binding of "free" Hb released into the circulation during the process of intravascular hemolysis. By capturing the liberated Hb, Hp protects against toxic effects associated with Hb, and it facilitates Hb clearance through endocytosis by the macrophage scavenger receptor CD163. 2 Later studies of human and primate plasma revealed variant forms of Hp as well as the existence of an Hp-related protein (Hpr) that recently has been shown also to bind Hb. As highlighted in this review, novel functions of Hp depend on high-affinity interactions with Hb and lipoprotein and subsequent receptor recognition of the resulting complexes. Toxicity of hemoglobin released during intracellular hemolysisIntravascular hemolysis, which accounts for approximately 10% to 20% of total red blood cell destruction, 3 changes Hb from being an intracellular O 2 /CO 2 transporter to a highly toxic substance in plasma. This toxicity arises from the heme iron, which can react with endogenous hydrogen peroxide to produce free radicals, which in turn may cause severe oxidative tissue damage, 4 particularly in the kidney. 5 In addition to the oxidative toxicity of Hb, Hb is a potent scavenger of nitric oxide (NO), a signaling molecule that functions as a critical regulator of smooth muscle relaxation, endothelial adhesion molecule expression, and platelet activation and aggregation. 6,7 The reaction of Hb with NO is fast and irreversible, leading to the production of nitrate and methemoglobin. If allowed to occur, this Hbmediated consumption of vascular NO, referred to as NOscavenging, thus limits the bioavailabili...

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“…The defect in null mice is liver specific. In addition to the liver, the lung is also able to mount an APR to LPS (26). An analysis of APP gene expression in the lung at 12 h post-LPS treatment was performed to determine whether the lack of a response in C/EBP␣ Ϫ/Ϫ mice was liver specific (Fig.…”

Section: Resultsmentioning

confidence: 99%

C/EBPα Is Critical for the Neonatal Acute-Phase Response to Inflammation

Burgess-Beusse¹,

Darlington

1998

Molecular and Cellular Biology

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Members of the C/EBP (CCAAT/enhancer binding protein) family of transcription factors play important roles in mediating the acute-phase response (APR), an inflammatory process resulting from infection and/or tissue damage. Among the C/EBP family of proteins, C/EBP␤ and -␦ were thought to be the primary mediators of the APR. The function of C/EBP␣ in the APR has not been fully characterized to date. Here, we investigate the role of C/EBP␣ in the APR by using neonatal mice that lack C/EBP␣ expression. Northern blot analysis of acute-phase protein gene expression in neonatal mice treated with purified bacterial lipopolysaccharide or recombinant interleukin 1␤ as an inflammation stimulus showed a strong APR in wild-type mice, but a response in C/EBP␣ null animals was completely lacking. The C/EBP␣ knockout and wild-type mice demonstrated elevations in C/EBP␤ and -␦ mRNA expression and DNA binding as well as increased DNA binding of NF-B, all of which are known to be important in the APR. Null mice, however, failed to activate STAT3 binding in response to lipopolysaccharide. Our results provide the first evidence that C/EBP␣ is absolutely required for the APR in neonatal mice, is involved in STAT3 regulation, and cannot be compensated for by other C/EBP family members.

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Extrahepatic expression of plasma protein genes during inflammation

Cited by 90 publications

References 30 publications

Transcript-Selective Translational Silencing by Gamma Interferon Is Directed by a Novel Structural Element in the Ceruloplasmin mRNA 3′ Untranslated Region

Transcript-Selective Translational Silencing by Gamma Interferon Is Directed by a Novel Structural Element in the Ceruloplasmin mRNA 3′ Untranslated Region

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

C/EBPα Is Critical for the Neonatal Acute-Phase Response to Inflammation

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