Journal of Heredity Advance Access first published online on June 15, 2007
This version published online on June 27, 2007
Journal of Heredity, doi:10.1093/jhered/esm025
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Comparison of the Human and Canine Cytokines IL-1(
/ß) and TNF- to Orthologous Other Mammalians
From the Small Animal Clinic, University of Veterinary Medicine, Bischofsholer Damm 15, 30137 Hanover, Germany (Soller, Escobar, Willenbrock, Eberle, and Nolte); and the Centre for Human Genetics, University of Bremen, Leobener Strasse ZHG, 28359 Bremen, Germany (Soller, Escobar, Willenbrock, Janssen, and Bullerdiek)
Address correspondence to Dr. I. Nolte at the address above, or e-mail: inolte{at}klt.tiho-hannover.de.
The cytokines interleukin-1 (IL-1
and IL-1ß) and the tumor necrosis factor- (TNF-) both play a major role in the initiation and regulation of inflammation and immunity responses. Polymorphisms within the gene sequences of these cytokines IL-1 and TNF- have been proposed to play an important role in the pathogenesis of certain diseases. Affecting nearly every organ, various diseases, including some cancers, are described to be associated with an increased level of IL-1 and TNF- proteins, for example, solid tumors, hematologic malignancies, malignant histiocytosis, autoimmune disorders, Alzheimer's disease, Parkinson's disease, sepsis, and rheumatoid arthritis. Regarding genetic backgrounds and pathways, numerous canine diseases show close similarities to their human counterparts. As a genetic model, the dog could be used to unravel the genetic mechanisms, for example, in particular the predispositions, the development, and progression of cancer and metabolic diseases. The identity comparison of gene and protein sequences of different species could be used to elucidate the structure and function of the genes and proteins by identifying the evolutionary conserved regions and domains. Herein we analyzed in detail the mRNA and protein structures and identities of the present known mammalian (human, canine, murine, rat, ovine, equine, feline, porcine, and bovine) TNF-, IL-1, and IL-1ß mRNAs and proteins. Additionally, based on the canine genome sequence, we derived in silico the complete mRNA structures of the IL-1 and IL-1ß mRNAs.
The cytokines interleukin-1 (IL-1
and IL-1ß) and tumor necrosis factor- (TNF-) are primarily secreted by monocytes and macrophages and act as potent multifunctional cytokines in abundant signal transduction processes during immune response and inflammation, acting as proinflammatory proteins. These cytokines bind to cell-surface receptors inducing the activation of different transcription factors, for example, AP1, CREB, and NF-
B for regulation of immediate early genes. In detail, IL-1 and IL-1ß will bind to membrane-bound receptor IL-1RI, whereas 2 distinct receptors TNF-R55 and TNF-R60 exist for TNF-. Although both receptors for IL-1 and TNF- are structurally unrelated, they operate both in a similar biological manner (Brockhaus et al. 1990; Eisenberg et al. 1991; Dinarello 1996).
In particular, NFB-dependent signaling pathways play a key role for inflammatory responses caused by injury and infection stimuli. In mammals, 5 NF-B proteins, RelA, RelB, c-Rel, NF-B1, and NF-B2 were described, which form homo- and heterodimer complexes in the cytoplasm. NF-B proteins are inactivated by binding the inhibitory protein IB. IL-1 and TNF- are able to trigger phosphorylation and ubiquitinylation pathways to degrade the IB protein having a releasing effect for NF-B and thus inducing the transcription of several genes in the nucleus (for review see Beutler and Cerami 1989; Stylianou and Saklatvala 1998; Alberts et al. 2002).
IL-1 and IL-1ß both belong to the same gene family of Interleukin-1 and are translated as precursor proteins with a molecular weight of 31 kDa. The processing of the isoforms of proIL-1 and proIL-1ß by cellular proteases results in a mature form of the protein of approximately 17 kDa (Dinarello 1996).
Intracellular proIL-1 is fully active and cleaved by Ca2+-dependent membrane-associated cysteine proteases called calpains to IL-1 propiece (16 kDa), which then is able to bind to nuclear DNA, and to mature IL-1, which is released to the extracellular compartment (Kobayashi et al. 1990; Dinarello 1996). IL-1 shows significant antitumor activity on solid tumor cells in vitro and in vivo (Braunschweiger et al. 1988). It also has an effect on bone marrow cells to produce colony-stimulating factors (Bagby et al. 1986).
ProIL-ß remains in the cytoplasm until it is cleaved by the cysteine proteinase IL-1ß–converting enzyme to the IL-1ß propiece (16 kDa) and the biologically active 17-kDa mature IL-1ß protein. Either protein is able to bind the cell membrane or to be transported out of the cell (Dinarello 1996).
The TNF- protein exists in 2 forms: a soluble form of 157 amino acids (aa) (17 kDa) cleaved at aa position 76 and 77 by ADAM17 and as a membrane-bound form of 233 aa (26 kDa). Additionally, it acts as a potent pyrogen when stimulated by IL-1. Also TNF- can induce cell death of certain tumor cells (Beutler and Cerami 1989).
The human nucleotide sequences of the IL-1 and IL-1ß genes contain 6 introns and 7 exons. The genes are located on HSA 2q14 (Furutani et al. 1986; Webb et al. 1986; Modi et al. 1988; Lafage et al. 1989). In humans, the TNF- gene consists of 3 introns and 4 exons and spans approximately 3 kb and was mapped on HSA 6p21 (Nedwin et al. 1985; Spies et al. 1986).
Cytokines are considered to play a major role in the pathogenesis of several diseases.
Polymorphisms within the promoter and/or enhancer regions within the gene sequences of IL-1/ß and TNF- are proposed to play a role in the development and pathogenesis of Alzheimer's disease and Parkinson's disease (Nicoll et al. 2000; McGeer PL and McGeer EG 2001; Mattila et al. 2002), as well as nonsmall cell lung cancer (Zienolddiny et al. 2004), tuberculosis (Correa et al. 2005), sepsis, and rheumatoid arthritis (Cox et al. 1999; Ruuls and Sedgwick 1999). Also the production of large quantities of IL-1 and TNF- cytokines in T-cells are expected to be responsible for the development and progression of certain autoimmune and tumor diseases like in human the Langerhans' cell histiocytosis and the canine malignant histiocytosis (Ramsey et al. 1996; Egeler et al. 1999; Tazi et al. 2000; Affolter and Moore 2002; Arico 2006).
Some human and canine diseases show similarities, concerning the dysfunction of regulation of the immune system and inflammatory processes and the genetic pathways for the development of neoplastic diseases, for example, malignant histiocytosis (Ramsey et al. 1996; Affolter and Moore 2002). Comparative analyses of canine cytokine genes to the known gene information of other mammalians could be used to clarify the mechanisms of etiology and pathogenesis. The knowledge gained by the species comparison could help to evaluate the different species as appropriate models for research studies opening new aspects for experimental and therapeutic approaches.
In Figure 1A and B, the IL-1, IL-1ß, and TNF- mRNA sequences of 7 mammalians currently present at the National Center for Biological Information (NCBI) database (October 2006) are shown in detail (including the present information on the coding sequences (CDS), 5' untranslated regions [UTRs] and 3'UTRs). Additionally, we derived in silico the complete structures of the IL-1 and IL-1ß mRNAs using the released canine genome sequence (Lindblad-Toh et al. 2005).
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For CDS and protein identity analyses, we used the described sequences from human, dog, mouse, cat, pig, cattle, rat, horse, and sheep and deduced, if necessary, the corresponding parts for analysis. The in silico analysis were done using LASERGENE software programs (DNASTAR, Madison, WI).
The first publications of human and murine IL-1 gene sequences (NM_000575
[GenBank]
, NM_010554
[GenBank]
) were done at the middle of the 1980s. The human CDS is composed of 816 bp and 813 bp for the murine sequence (Furutani et al. 1985; Lomedico et al. 1984; March et al. 1985). Straubinger et al. characterized the canine (798 bp) and feline (813 bp) CDS and parts of 3'UTR for the IL-1 mRNAs (NM_001003157, AF047012
[GenBank]
) spanning exon 2–7, respectively. Two different splice variant transcripts of canine, feline, and porcine IL-1 were described to be found in total RNA from lipopolysaccharide-stimulated lung macrophages. One transcript was identified as a new mRNA splice variant of canine IL-1 missing the 175 bp of exon 5 (Straubinger et al. 1999). Due to the deletion of exon 5, the calpain cleavage site is lacking, and calpain is unable to cleave the precursor protein to the mature protein. In previous studies aimed at a single-nucleotide polymorphism screening analysis in canine cytokine mRNA transcripts of IL-1(/ß) and TNF-, we cloned the IL-1 mRNAs adding new information on the 5'UTR (complete exon 1 and parts of exon 2) and additional parts for the 3'UTR (Soller et al. 2006). We also found both splice variants IL-1a (DQ923806
[GenBank]
) and the splice variant bearing the exon 5 deletion (EF068230
[GenBank]
): We analyzed them in detail and submitted them to the NCBI database completing the known information due to the fact that the sequences describing the splice variant were not submitted to the databases by the respective author. The genetic structure and organization of all compared IL-1a cytokines are highly conserved among the different mammalians. The detailed sequence comparisons (Figure 1A) showed that all cytokine transcripts of the different species with exception of the feline and ovine sequences are composed of equal number of 7 exons. The ovine and feline exceptions are the missing of the sequence information coding for exon 1, probably due to the transcripts have not been completely characterized up to date.
The identities of the canine IL-1 CDS (NM_001003157) to the CDS sequences of other species vary between mouse CDS (NM_008361
[GenBank]
) 43.9%, rat CDS (D00403
[GenBank]
) 69.3%, human CDS (NM_000575
[GenBank]
) 79.6%, horse CDS (U92480
[GenBank]
) 84.8%, and cat CDS (AF047012
[GenBank]
) 88.8% (Table 1). Respectively. the identities of the canine IL-1 protein sequence (ABJ51907
[GenBank]
) to the protein sequences of the other species vary between mouse protein (NP_034684
[GenBank]
) 57.1%, rat protein (BAA00306
[GenBank]
) 59.6%, human protein (NP_000566
[GenBank]
) 68.5%, horse protein (AAC39255
[GenBank]
) 79.3%, and cat protein (AAC03067
[GenBank]
) 82.7% (Table 1).
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The IL-1
proteins of all mammalians show strong conservation of the predicted calpain cleavage site (-KPRSV-), located between the arginine residue at position 108 and the serine residue at position 109 of the canine protein. The average IL-1 protein size of the described mammalians is about 270 aa. The protein size range about 266 aa (dog, sheep), 268 aa (horse, rat), 269 aa (cattle) to 271 aa (mouse, cat, pig), and 272 aa (human). Correspondingly, the human (BC_008678) and the murine IL-1ß (NM_008361 [GenBank] ) CDS and protein sequences (Auron et al. 1984; Gray et al. 1986; Telford et al. 1986) were analyzed by identity comparison and evaluated with the canine, feline, porcine, bovine, equine, ant rat sequences.
As described for IL-1, we cloned the canine IL-1ß mRNA, analyzed it in detail, and submitted it to the NCBI database adding new information on the 3'UTR to the present data. As shown in Figure 1A, again the genetic structure and organization of all compared IL-1ß cytokine transcripts are highly conserved among the different analyzed mammalians. The detailed sequence data comparison (Figure 1A) showed that all analyzed mammalian cytokine transcripts, with the exception of the cloned canine sequences (NM_001037971 and DQ923807
[GenBank]
), are composed of equal number of 7 exons. The canine sequences (NM_001037971 and DQ923807
[GenBank]
) are missing the sequence information for the 5'UTR (exon 1) that have not been completely cloned until now. Taking into account the in silico-derived structure of the canine IL-1ß (Figure 1A), the dog shows also 7 exons with a highly conserved structure to the compared species.
The CDS identities of the canine IL-1ß (NM_001037971, DQ923807 [GenBank] ) to the sequences of the other mammalians vary between mouse CDS (NM_008361 [GenBank] ) 71.7%, human CDS (BC_008678) 76.4%, horse CDS (U92481 [GenBank] ) 79.3%, and cat CDS (M92060 [GenBank] ) 83.8% (Table 1). The identities of the canine IL-1ß protein to the protein sequences of the other mammalians vary between mouse (NP_032387 [GenBank] ) 58.3%, human protein (CAA28185 [GenBank] ) 62.8%, horse protein (AAC39256 [GenBank] ) 67.3%, and cat protein (AAA30814 [GenBank] ) 74.0% (Table 1).
In the canine IL-1ß protein, a ß-strand motif at aa residue position 232–240 (-PNWYISTSQ-) is highly conserved in the other described mammalians human, mouse, rat, cat, pig, sheep, horse, and cattle. The IL-1ß protein sizes of the different species vary between 267 aa (cattle, dog) and 270 aa (human).
The genetic structure and organization of all compared TNF- cytokine transcripts are also highly conserved among the different species. The detailed sequence comparisons (Figure 1B) showed that all TNF- transcripts of the different species are composed of 4 exons. All described sequences, with the exception of feline (M92061
[GenBank]
), bovine (NM_173966
[GenBank]
), and equine cDNAs (BAA88349
[GenBank]
), show the full mRNA sequences including the CDS, 5'UTR, and 3'UTRs. The feline, bovine, and equine sequences exceptions are the missing of the sequence information coding for the 5'UTRs and 3'UTRs, surely due to the missing complete characterization of the respective mRNA transcripts.
The highest identity values among the analyzed cytokines show the CDS and proteins of TNF-. The canine CDS for TNF- (AY423389
[GenBank]
) shows identities from mouse CDS (X02611
[GenBank]
) 80.4%, sheep CDS (NM_001024860) 83.9%, pig CDS 85.5% (NM_214022
[GenBank]
), to human CDS 90.8% (M26331
[GenBank]
), and cat CDS 93.3% (M92061
[GenBank]
) (Table 1). Respectively, the identities of the canine TNF- protein sequence (AAR27885
[GenBank]
) to the protein sequences of the other species vary between mouse protein (CAA26457
[GenBank]
) 78.2%, sheep protein (NP_001020031) 79.1%, pig protein (NP_999187
[GenBank]
) 85.5%, human protein (AAA36758
[GenBank]
) 91.0%, and cat protein (AAA30818
[GenBank]
) 94.4%. The TNF- protein sizes vary between 233 aa (pig and sheep), 234 aa (human, dog, cat and rat) to 235 aa (cattle), and 236 aa (mouse).
The overall described cytokine identity values (Table 1) of the analyzed CDS and the derived proteins show a wide variance from 43.9% to 93.43% among the CDS and from 57.1% to 94.4% for the analyzed proteins.
The described mammalian cytokine transcript and protein comparison data emphasizes the relevance of structural comparative analysis of genes and proteins for the development of therapeutic strategies aimed at the development of therapeutic approaches targeting canine disorders. The observed overall cytokine identities are variable among the different species analyzed. In particular, the performed protein alignments of the cytokines IL-1 and TNF- showed highly conserved protein regions and domains of the compared elements among the mammalian species. In spite of the observed high variability in terms of nucleotide sequence identity, the structure of the analyzed genes is highly conservative.
The described properties of the cytokine genes IL-1 and TNF- and their described role in the development of tumor and metabolic diseases offer various possibilities for new approaches and applications and also for existing therapy concepts. The highly conserved structure of the cytokine proteins seen in mammalians allows knowledge transfer of already established experimental data and approaches from one mammalian species to another due to the fact that essential protein properties are comparable. It is to expect that future therapeutic approaches targeting cytokine-mediated diseases in humans and dogs will benefit from each other.
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Acknowledgments |
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This research was supported by a grant of the Gesellschaft zur Förderung Kynologischer Forschung.
This paper was delivered at the 3rd International Conference on the Advances in Canine and Feline Genomics, School of Veterinary Medicine, University of California, Davis, CA, August 3–5, 2006.
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Footnotes |
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Corresponding Editor: Steven Hannah
The symposium paragraph for this article has been inserted.
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