IL1HY1: A Novel Interleukin-1 Receptor Antagonist Gene

Mulero, Julio J.; Pace, Ann M.; Nelken, Sarah T.; Loeb, Deborah B.; Correa, Tanis R.; Drmanac, Radoje; Ford, J. E.

doi:10.1006/bbrc.1999.1440

Cited by 90 publications

(65 citation statements)

References 23 publications

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“…Although the function of IL-1L1 remains undescribed (Barton et al 2000), its abundant expression in skin and vaginal epithelium suggests that it may be involved in epithelial cell differentiation (Mulero et al 1999). IL-1L1 expression was elevated 24 h after E 2 administration, similar to other differentiation markers such as CK1 (data not shown).…”

Section: Il-1 Signalingmentioning

confidence: 87%

Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol

Miyagawa¹,

Suzuki²,

Katsu³

et al. 2004

Journal of Molecular Endocrinology

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Developmental exposure to a synthetic estrogen, diethylstilbestrol (DES), induces carcinogenesis in human and laboratory animals. In mice, neonatal DES treatment induces persistent proliferation and keratinization of the vaginal epithelium, even in the absence of the ovaries, resulting in cancerous lesions later in life. To understand the mechanisms underlying this persistent cell proliferation and differentiation, we characterized the gene expression patterns in the neonatally DES-exposed mouse vagina using DNA microarray and real-time quantitative RT-PCR. We found that genes related to cellular signaling, which are candidates for mediating the persistent proliferation and differentiation, were altered, and genes related to the immune system were decreased in the neonatally DES-exposed mouse vagina. We also noted high expression of interleukin-1 (IL-1)-related genes accompanied by phosphorylation of JNK1. In addition, expression IGF-I and its binding proteins was modulated and led to phosphorylation of IGF-I receptor and Akt, which is one of the downstream factors of IGF-I signaling. This led us to characterize the expression as well as the phosphorylation status of IL-1 and IGF-I signaling pathway components which may activate the phosphorylation cascade in the vagina of mice exposed neonatally to DES. These findings give insight into persistent activation in the vagina of mice exposed neonatally to DES.

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Section: Il-1 Signalingmentioning

confidence: 87%

Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol

Miyagawa¹,

Suzuki²,

Katsu³

et al. 2004

Journal of Molecular Endocrinology

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“…In line with recent reports (24 -28), we have independently identified two novel IL-1 ligands based on sequence homology with IL-1ra, which we termed IL-1␦ and IL-1⑀. IL-1␦ corresponds to the reported sequences of IL1Hy1 (24), FIL1␦ (25), murine IL1H3 (26), IL-1RP3 (27) and IL-1L (28), whereas IL-1⑀ corresponds to IL1H1 (26) and IL-1RP2 (27). These novel IL-1s are strongly expressed in embryonic tissue and epithelial cells, such as skin keratinocytes.…”

Section: Two Novel Il-1 Family Members Il-1␦ and Il-1⑀ Function As mentioning

confidence: 89%

Two Novel IL-1 Family Members, IL-1δ and IL-1ε, Function as an Antagonist and Agonist of NF-κB Activation Through the Orphan IL-1 Receptor-Related Protein 2

Debets

Timans

Homey

et al. 2001

The Journal of Immunology

240

224

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IL-1 is of utmost importance in the host response to immunological challenges. We identified and functionally characterized two novel IL-1 ligands termed IL-1δ and IL-1ε. Northern blot analyses show that these IL-1s are highly abundant in embryonic tissue and tissues containing epithelial cells (i.e., skin, lung, and stomach). In extension, quantitative real-time PCR revealed that of human skin-derived cells, only keratinocytes but not fibroblasts, endothelial cells, or melanocytes express IL-1δ and ε. Levels of keratinocyte IL-1δ are ∼10-fold higher than those of IL-1ε. In vitro stimulation of keratinocytes with IL-1β/TNF-α significantly up-regulates the expression of IL-1ε mRNA, and to a lesser extent of IL-1δ mRNA. In NF-κB-luciferase reporter assays, we demonstrated that IL-1δ and ε proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1α and β or IL-18. However, IL-1ε activates NF-κB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1δ, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1ε response. In lesional psoriasis skin, characterized by chronic cutaneous inflammation, the mRNA expression of both IL-1 ligands as well as IL-1Rrp2 are increased relative to normal healthy skin. In total, IL-1δ and ε and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1αβ/receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.

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“…The new IL-1 family members, IL-1F5, IL-1F6, IL-1F8, and IL-1F9, were identified by different research groups on the basis of sequence homology, three-dimensional structure, gene location, and receptor binding [3][4][5][6][7][8]. These new ligands share 21% to 37% amino acid homology with IL-1β and IL-1Ra, with the exception of IL-1F5, which has 52% homology with IL-1Ra, suggesting that IL-1F5 may be an endogenous antagonist.…”

Section: Potential Functions Of Interleukin-1rrp2-binding Cytokinesmentioning

confidence: 99%

Cytokines in the rheumatic diseases

Arend¹,

Gabay²

2004

Rheumatic Disease Clinics of North America

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A better understanding of cytokine biology over the last two decades has allowed the successful development of cytokine inhibitors against tumour necrosis factor and interleukin (IL)-1 and IL-6. The introduction of these therapies should be considered a breakthrough in the management of several rheumatic diseases. However, many patients will exhibit no or only partial response to these therapies, thus emphasising the importance of exploring other therapeutic strategies. In this article, we review the most recent information on novel cytokines that are often members of previously described cytokine families such as the IL-1 superfamily (IL-18 and IL-33), the IL-12 superfamily (IL-27 and IL-35), the IL-2 superfamily (IL-15 and IL-21), and IL-17. Several data derived from experimental models and clinical samples indicate that some of these cytokines contribute to the pathophysiology of arthritis and other inflammatory diseases. Targeting of some of these cytokines has already been tested in clinical trials with interesting results. IntroductionCytokines mediate a wide variety of immunologic actions and are key effectors in the pathogenesis of several human autoimmune diseases. In particular, their pleiotropic functions and propensity for synergistic interactions render them intriguing therapeutic targets. Single-cytokine targeting has proven useful in several rheumatic disease states, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and across the spectrum of spondyloarthropathies. Strong pre-clinical and clinical evidence implicates tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 as critical cytokine effectors in inflammatory synovitis. However, non-responders or partial clinical responders upon TNF blockade are not infrequent and disease usually flares up upon discontinuation of treatment. Registry datasets confirm gradual attrition of patients who do reach stable TNF blockade. Crucially, clinical remission is infrequently achieved. Thus, considerable unmet clinical needs remain. This has provoked considerable enterprise in establishing the presence and functional activities of novel cytokines in the context of synovitis. In this short review, we consider the biology and relevant pathophysiology of several novel cytokines present and implicated in synovial processes. Novel interleukin-1-related cytokinesThe first members of the IL-1 family of cytokines included IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), and IL-18. Seven additional members of the IL-1 family of ligands have been identified on the basis of sequence homology, threedimensional structure, gene location, and receptor binding [1,2]. A new system of terminology has been proposed for the IL-1 cytokines such that IL-1α, IL-1β, IL-1Ra, and IL-18 become IL-1F1, IL-1F2, IL-1F3, and IL-1F4, respectively. The new IL-1 cytokines are termed IL-1F5 through IL-1F11, the latter representing IL-33. IL-1F6, IL-1F8, and IL-1F9 are ligands for the IL-1R-related protein 2 (IL-1Rrp2), requiring the co-receptor IL-1RAcP for activity...

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IL1HY1: A Novel Interleukin-1 Receptor Antagonist Gene

Cited by 90 publications

References 23 publications

Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol

Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol

Two Novel IL-1 Family Members, IL-1δ and IL-1ε, Function as an Antagonist and Agonist of NF-κB Activation Through the Orphan IL-1 Receptor-Related Protein 2

Cytokines in the rheumatic diseases

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