Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5

Sieburth, Derek; Jabs, Ethylin Wang; Warrington, Janet A.; Li, X.; Lasota, Jerzy; LaForgia, Sal; Kelleher, K.; Huebner, Kay; Wasmuth, John J.; Wolf, Stanley F.

doi:10.1016/s0888-7543(05)80283-6

Cited by 120 publications

(52 citation statements)

References 23 publications

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“…54 Antigenpresenting cells, such as dendritic cells and macrophages, are the primary producers of IL-12, a heterodimeric cytokine consisting of p40 and p35 subunits that arise as two different gene products. 55 p35 is constitutively transcribed, is regulated posttranslationally, 56 and is not secreted independently. In contrast, p40 production is regulated by inflammatory effectors, often to high levels, including during infection with Neisseria meningitides 57 or in autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

Stearns-Kurosawa

Lupu

Taylor

et al. 2006

The American Journal of Pathology

103

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Studies that define natural responses to bacterial sepsis assumed new relevance after the lethal bioterrorist attacks with Bacillus anthracis (anthrax), a spore-forming, toxigenic gram-positive bacillus. Considerable effort has focused on identifying adjunctive therapeutics and vaccines to prevent future deaths, but translation of promising compounds into the clinical setting necessitates an animal model that recapitulates responses observed in humans. Here we describe a nonhuman primate (Papio c. cynocephalus) model of B. anthracis infection using infusion of toxigenic B. anthracis Sterne 34F2 bacteria (5 ؋ 10 5 to 6.5 ؋ 10 9 CFU/kg). Similar to that seen in human patients, we observed changes in vascular permeability, disseminated intravascular coagulation, and systemic inflammation. The lung was a primary target organ with serosanguinous pleural effusions, intra-alveolar edema, and hemorrhagic lesions. This animal model reveals that a fatal outcome is dominated by the host septic response, thereby providing important insights into approaches for treatment and prevention of anthrax in humans. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

Stearns-Kurosawa

Lupu

Taylor

et al. 2006

The American Journal of Pathology

103

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“…13 Recently, the genomic sequence of the IL-12 p40 subunit was determined. 14 Whereas no polymorphisms were found in the coding region of this gene, several intronic polymorphisms and a TaqI polymorphism in the 3 0 UTR at position 1188 were identified.…”

Section: Introductionmentioning

confidence: 99%

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

et al. 2002

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Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. We evaluated whether a TaqI polymorphism in the 3 0 UTR of the IL-12 p40 gene affects secretion of IL-12 in vitro, and whether this polymorphism is associated with susceptibility to Crohn's disease (CD). IL-12 p40 and p70 secretion by monocytes in relation to genotype was determined in 63 healthy donors. Genotype and allele frequencies of the TaqI polymorphism in 150 CD patients were compared with 145 ethnically matched healthy controls (HC). No significant association was found between genotype and IL-12 p40 secretion after stimulation of monocytes with SAC+IFNg. In contrast, increasing IL-12 p70 secretion was found across the categories of noncarriers, heterozygotes and homozygotes for the variant allele (median values 7 SEM: 147 7 27, 282 7 51 and 482 7 34 pg/ ml, respectively; Po0.005). The allele and genotype frequencies of this polymorphism in patients with CD did not differ statistically significantly from HC. The presence of a TaqI polymorphism in the IL12 p40 3 0 UTR correlates with increased in vitro IL-12 p70, but not p40 secretion. While this polymorphism does not appear to be correlated with susceptibility to CD in the limited population of patients tested here, it could influence the occurrence of the disease in certain subsets of patients.

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“…It is unique among numbered cytokines in that it exists as a heterodimer of two glycosylated polypeptides (termed p35 and p40) that are encoded by genes on separate chromosomes (2). The p35 shares structural similarities with the cytokines IL-6 and G-CSF (3), whereas p40 is structurally related to the IL-6R (4).…”

mentioning

confidence: 99%

“…We (8) and others (9) have shown that p35 expression is the limiting factor controlling production of IL-12 in APC, although, even under optimal conditions, p40 2 may predominate. In fact, recent studies suggest that the IL-12 response is a carefully orchestrated temporal balance between antagonistic p40 2 and IL-12 heterodimers, with p40 2 appearing first, followed by IL-12 (10).…”

mentioning

confidence: 99%

Disparate Intracellular Processing of Human IL-12 Preprotein Subunits: Atypical Processing of the P35 Signal Peptide

Murphy

Hayes

Burd

2000

The Journal of Immunology

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IL-12 is a heterodimeric cytokine produced by APC that critically regulates cell-mediated immunity. Because of its crucial function during immune responses, IL-12 production is stringently regulated, in part through transcriptional control of its p35 subunit, which requires the differentiative effects of IFN-γ for expression. To determine whether post-transcriptional aspects of IL-12 production might be regulated, we examined intracellular protein processing of each subunit. We report here that p40 and p35 subunits are processed by disparate pathways. Whereas processing of p40 conforms to the cotranslational model of signal peptide removal concomitant with translocation into the endoplasmic reticulum (ER), processing of p35 does not. Translocation of the p35 preprotein into the ER was not accompanied by cleavage of the signal peptide; rather, removal of the p35 signal peptide occurred via two sequential cleavages. The first cleavage took place within the ER, and the cleavage site localized to the middle of the hydrophobic region of the signal peptide. Although the preprotein was glycosylated upon entry into the ER, its glycosylation status did not affect primary cleavage. Subsequently, the remaining portion of the p35 signal peptide was removed by a second cleavage, possibly involving a metalloprotease, concomitant with additional glycosylation and secretion. Secretion could be inhibited by mutation of the second cleavage site or by inhibition of glycosylation with tunicamycin. In contrast, p40 secretion was not affected by inhibition of glycosylation. Our findings demonstrate that IL-12 subunits are processed by disparate pathways and suggest new modalities for regulation of IL-12 production.

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Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5

Cited by 120 publications

References 23 publications

Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

Disparate Intracellular Processing of Human IL-12 Preprotein Subunits: Atypical Processing of the P35 Signal Peptide

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