The First Cytokine Sequence Within Cartilaginous Fish: IL-1β in the Small Spotted Catshark (<i>Scyliorhinus canicula</i>)

Bird, Steve; Wang, Tiehui; Zou, Jun; Cunningham, Charlie; Secombes, Chris J.

doi:10.4049/jimmunol.168.7.3329

Cited by 105 publications

(42 citation statements)

References 50 publications

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“…In pro-IL-1␤, the highest protection from exchange in this region is the portion corresponding to the turn between strands 1 and 2, and strand 2 itself (125-135, 9 -19). Overlapping residues (12)(13)(14)(15)(16)(17)(18)(19)(20) are protected from exchange after 48 h as observed by H/D NMR in the mature protein (49). Either the pro-IL-1␤ structure preserves these turn contacts, or the steric bulk of the N-terminal region helps limit solvent exchange in the C-terminal region.…”

Section: The N Terminus Region Of Pro-il-1␤ (Residues 1-116) Displaysmentioning

confidence: 97%

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Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Hailey¹,

Andersen³

et al. 2009

Journal of Biological Chemistry

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Interleukin-1␤ (IL-1␤) is a master cytokine involved in initiating the innate immune response in vertebrates (Dinarello, C. A. (1994) FASEB J. 8, 1314 -1325). It is first synthesized as an inactive 269-residue precursor (pro-interleukin-1␤ or pro-IL-1␤). Pro-IL-1␤ requires processing by caspase-1 to generate the active, mature 153-residue cytokine. In this study, we combined hydrogen/deuterium exchange mass spectrometry, circular dichroism spectroscopy, and enzymatic digestion comparative studies to investigate the configurational landscape of pro-IL-1␤ and the role the N terminus plays in modulating the landscape. We find that the N terminus keeps pro-IL-1␤ in a protease-labile state while maintaining a core region of stability in the C-terminal region, the eventual mature protein. In mature IL-1␤, this highly protected region maps back to the area protected earliest in the NMR studies characterizing an on-route kinetic refolding intermediate. This protected region also encompasses two important functional loops that participate in the IL-1␤/receptor binding interface required for biological activity. We propose that the purpose of the N-terminal precursor region in pro-IL-1␤ is to suppress the function of the eventual mature region while keeping a structurally and also functionally important core region primed for the final folding into the native, active state of the mature protein. The presence of the self-inhibiting precursor region provides yet another layer of regulation in the life cycle of this important cytokine.Nearly all cell types respond to interleukin (IL)-1␤, 4 in a very sensitive manner, via binding to the interleukin-1 receptor type 1 (IL-1RI) (2). Although essential in the immune response, overproduction of IL-1␤ can lead to both acute (sepsis) as well as chronic (rheumatoid arthritis, atherosclerosis, obesity, and diabetes) disease states (3). Thus, the expression, activation, and secretion of this cytokine are tightly controlled (4). Although many cell types express IL-1␤, it is predominately produced and secreted by monocytes and macrophages (1). The protein is synthesized as a biologically inactive 269-residue precursor molecule, pro-interleukin-1␤ (pro-IL-1␤), and the 153-residue active mature IL-1␤ is generated from the C-terminal domain. Processing of the proprotein involves the recently discovered NALP-1 and NALP-3 inflammasomes, which are responsible for activating procaspase-1 (5). The inflammasome function is integral in wound repair as well as for combating infection (6 -9).In vivo, the 31-kDa pro-IL-1␤ precursor is processed to the active C-terminal 17-kDa form by the interleukin-1 converting enzyme, caspase-1 (10, 11). Caspase-1 is a cysteine protease that recognizes two cleavage sites in pro-IL-1␤, the Asp 27 2Gly 28 and Asp 116 2Ala 117 peptide bonds (Fig. 1A). These cleavage sites are conserved across mammals (12-14). The activation pathway is believed to proceed with cleavage first at Asp 27 2Gly 28 (site 1) followed by Asp 116 2Ala 117 (site 2). These processing events lead ...

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Section: The N Terminus Region Of Pro-il-1␤ (Residues 1-116) Displaysmentioning

confidence: 97%

“…1A). These cleavage sites are conserved across mammals (12)(13)(14). The activation pathway is believed to proceed with cleavage first at Asp 27 2Gly 28 (site 1) followed by Asp 116 2Ala 117 (site 2).…”

mentioning

confidence: 99%

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Hailey¹,

Andersen³

et al. 2009

Journal of Biological Chemistry

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“…Since then, the gene has been cloned in a number of other fish including the first sequence from a cartilaginous species , Bird et al 2002. In vitro and in vivo studies with trout recombinant IL-1 (rIL-1 ), to date, have demonstrated the potency of this molecule in inducing a range of immune genes (e.g.…”

Section: Introductionmentioning

confidence: 99%

Recombinant interleukin-1 beta activates the hypothalamic-pituitary-interrenal axis in rainbow trout, Oncorhynchus mykiss

Holland

Pottinger²,

Secombes

2002

Journal of Endocrinology

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The present study provides the first direct evidence that implicates fish cytokines as the effector molecules by which the immune system signals the neuroendocrine system and activates the hypothalamic-pituitary-interrenal stress axis. I.p. injections of trout recombinant interleukin-1 (rIL-1 ) or E. coli lipopolysaccharide (LPS), at concentrations known to induce immune/inflammatory responses in vivo (0·1-0·6 nmol/kg and 1·3 mg/kg respectively), significantly elevated plasma cortisol levels in a dose-and/or time-dependent manner. However, in contrast to general stress responses in fish, under the conditions employed in this study, no specific treatment effects on plasma glucose levels could be demonstrated. The trout IL-1 peptides (P1 and P3), which are homologous to receptor-binding sequences of human IL-1 , failed to influence the prevailing cortisol concentration even though an equivalent dose has been found to have immunostimulatory properties in vivo. Blockade of endogenous ACTH release by administration of the synthetic glucocorticoid dexamethasone prevented the rIL-1 /LPS-mediated elevation of plasma cortisol, suggesting that IL-1 and LPS modulate cortisol secretion via effects at the level of the hypothalamic-pituitary axis. These data indicate that, with respect to IL-1 , cytokine signalling between the immune and neuroendocrine systems in mammals appears to be conserved in lower vertebrates.

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“…3¢-RACE-PCR was performed using primers F1/ ADAP and F2/ADAP to amplify the full length sequence of the coding region and the 3¢-UTR [39]. For 5¢-RACE, cDNA was tagged with oligo(dC)n at the 5¢-end with terminal deoxynucleotidyl transferase (Promega) and used as template for seminested PCR amplification with primers oligo-dG/R2 and oligo-dG/R3 [39]. The cycling programs for RACE-PCR were 5 cycles of 94°C for 20 s, 72°C for 2 min; 32 cycles of 94°C for 20 s, 62°C for 20 s, 72°C for 45 s; followed by 1 cycle of 72°C for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Identification and expression analysis of an IL‐18 homologue and its alternatively spliced form in rainbow trout (Oncorhynchus mykiss)

Zou

Bird

Truckle

et al. 2004

European Journal of Biochemistry

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A homologue of interleukin 18 has been identified from rainbow trout, Oncorhynchus mykiss. The trout IL-18 gene spans 3.7 kb and consists of six exons and five introns, sharing the same gene organization with its human counterpart. The putative translated protein is 199 amino acids in length with no predicted signal peptide. Analysis of the multiple sequence alignment reveals a conserved ICE cut site, resulting in a mature peptide of 162 amino acids. The trout IL-18 shares 41-45% similarity with known IL-18 molecules and contains an IL-1 family signature motif. It is constitutively expressed in a wide range of tissues including brain, gill, gut, heart, kidney, liver, muscle, skin and spleen. Transcription is not modulated by lipopolysaccharide, poly(I:C) or trout recombinant IL-1b in primary head kidney leucocyte cultures and RTS-11 cells, a macrophage cell line. However, expression is downregulated by lipopolysaccharide and rIL-1b in RTG-2 cells, a fibroblast-like cell line. An alternatively spliced form of IL-18 mRNA has also been found and translates into a 182 amino acid protein with a 17 amino acid deletion in the precursor region of the authentic form. This alternatively spliced form is also widely expressed although much lower than the authentic form. Interestingly, its expression is upregulated by lipopolysaccharide and poly(I:C), but is not affected by rIL-1b in RTG-2 cells. The present study suggests that alternative splicing may play an important role in regulating IL-18 activities in rainbow trout.Keywords: interleukin 18; alternative splicing; expression; rainbow trout.In the last few years, major advances have occurred in the discovery of fish cytokine genes. This has been attributed mainly to the enormous progress made in genome projects for the Fugu and zebrafish genome, and the large increase of fish EST (expressed sequence tag) entries in the Genebank. Interleukin (IL) 18, produced mainly by activated macrophages, is an important cytokine with multiple functions in innate and acquired immunity [18][19][20]. One of the primary biological properties is to induce interferon gamma (IFN-c) synthesis in Th1 and NK cells in synergy with 22].It promotes T and NK cell maturation, activates neutrophils and enhances Fas ligand-mediated cytotoxicity [23][24][25].IL-18 structurally belongs to the IL-1 family but has low sequence homology with IL-1a, IL-1b and the IL-1 receptor antagonist (IL-Ra). It resembles IL-1b in many ways such as possessing a similar b-trefoil structure and secretion process but has distinct biological functions [18,26]. Like IL-1b, it is synthesized as an inactive precursor of approximately 24 kDa and is stored intracellularly. Activation and secretion of IL-18 is mainly effected through specific cleavage of the precursor after D35 by caspase 1, also termed IL-1b converting enzyme (ICE), which is believed to be one of the key processes regulating IL-18 bioactivity [27,28]. Some other enzymes, including caspase 3 and neutrophil proteinase 3, also cleave the IL-18 precursor to generate...

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The First Cytokine Sequence Within Cartilaginous Fish: IL-1β in the Small Spotted Catshark (Scyliorhinus canicula)

Cited by 105 publications

References 50 publications

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Recombinant interleukin-1 beta activates the hypothalamic-pituitary-interrenal axis in rainbow trout, Oncorhynchus mykiss

Identification and expression analysis of an IL‐18 homologue and its alternatively spliced form in rainbow trout (Oncorhynchus mykiss)

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