Molecular biology of IL11 and IL11 R

IL-11 cDNA and genomic sequences are well conserved among different species. IL-11 cDNAs contain a single open reading frame of 199 amino acids with a 21 amino acid signal peptide and a calculated molecular weight of 23 kDa. The cDNA encodes no cysteine residues and no N-linked glycosylation sites. The overall homology between mouse and human IL-11 cDNAs is 88% at the amino acid level and

86% at the nucleotide level. The human IL-11 gene has been mapped to the long arm of human chromosome 19 at 19ql3.3-13.4. The gene is 7 kb in length and consists of five exons and four introns. The 5'-flanking region contains several potential transcriptional control elements including AP-1, SP-1 and NF-kB. There are at least nine copies of ATTTA sequence in the 3'-flanking region. The IL-11 transcripts (2.5 and 1.5 kb) have been detected in primate and human bone marrow-derived stromal fibroblast cell lines, human lung fibroblast, tropho-blast, pulmonary and tracheal epithelial, cervical carcinoma, osteogenic sarcoma, megakaryoblastic and other leukemic cell lines. In addition, IL-11 transcripts have also been detected in human chondrocytes, synoviocytes and umbilical vein or adult aortic endothelial cells. The expression of the IL-11 transcripts in different cell types is constitutive but can be attenuated by different positive regulators including IL-1, transforming growth factor |3 (TGF(3), tissue plasminogen activator (t-PA), calcium iono-phore, respiratory syncytial virus (RSV), prostaglandin E| and E2 and forskolin, and negative regulators such as retinoic acid, IL-4, dexamethasone and heparin. The mechanisms of IL-11 gene expression mediated by different modulators have been shown to be at either the transcriptional or post-transcrip-tional level. In stromal fibroblasts, a 10 bp region (5'GGTGAGTCAG3') containing a consensus AP-1 site has been found to be responsible for the basal level transcription of the IL-11 gene and JunD is one of the major components of the DNA-protein transcriptional complexes. The 3'-UTR of IL-11 mRNA can function as a destabilizing component in IL-11 mRNA metabolism, possibly through the AUUUA motifs. In addition, the IL-11 5'-UTR and the IL-11 coding sequence, in conjunction with certain protein tyrosine kinases, are required for the stabilization of the IL-11 mRNA by IL-1 in stromal cells.

IL-11R consists of at least one ligand-binding sub-unit (IL-llRa) and a signal transduction subunit (gp 130). The mouse and human IL-11R cDNAs encode a 432 and a 422 amino acid polypeptide, respectively, with two potential N-linked glycosyl-ation sites and four cysteine residues in the extracellular domain. The position of these cysteine residues, the presence of a WSTWS motif in the extracellular domain and the lack of consensus sequences for tyrosine or serine/threonine kinases in the intracellular domain suggest that IL-llRa is a member of the hematopoietin receptor superfamily. The overall homology between mouse and human IL-1 IRa is 84% at the amino acid level and 85% at the nucleotide level. In the mouse genome, there are at least two IL-llRa genes, ILllRa and ILllRa2, that can potentially encode the IL-llRa. The IL-llRa gene is ubiquitously expressed while the IL1 lRa2 gene is only expressed in certain strains of mice in specific organs such as testis, lymph node and thymus. It appears that the molecular composition of IL-11R is more complicated than initially anticipated. Further biochemical molecular and in vivo knockout studies of IL-11R are underway to dissect the essential components for transducing IL-11 signals. Some of the known biochemical properties of IL-11 and IL-llRa are summarized in Table 1.

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