NORMAL GENOMIC

• Parrish-Novak J, Foster DC, Holly RD, Clegg CH
• Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses.
• J Leukoc Biol. 2002; 72: 856-63
• Display abstract

• Interleukin (IL)-21 was recently discovered using a functional cloning approach based on expression of its receptor. It is similar in domain organization and primary sequence to IL-2 and IL-15. Like these cytokines, IL-21 uses the common gamma chain of the IL-2/15 receptor, which forms a heterodimeric receptor complex with IL-21R. IL-21 is produced by activated T cells, and it influences proliferation of T and B cells and cytolytic activity of natural killer cells. The elucidation of the unique biological effects of IL-21 represents an intense area of interest in current cytokine biology.

• Kim MR et al.
• Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production.
• Blood. 2002; 100: 2330-40
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• We have identified and cloned a novel human cytokine with homology to cytokines of the interleukin-17 (IL-17) family, which we have termed human IL-17E (hIL-17E). With the identification of several IL-17 family members, it is critical to understand the in vivo function of these molecules. We have generated transgenic mice overexpressing hIL-17E using an apolipoprotein E (ApoE) hepatic promoter. These mice displayed changes in the peripheral blood, particularly, a 3-fold increase in total leukocytes consisting of increases in eosinophils, lymphocytes, and neutrophils. Splenomegaly and lymphoadenopathy were predominant and included marked eosinophil infiltrates and lymphoid hyperplasia. CCR3(+) eosinophils increased in the blood and lymph nodes of the transgenic mice by 50- and 300-fold, respectively. Eosinophils also increased 8- to 18-fold in the bone marrow and spleen, respectively. In the bone marrow, most of the eosinophils had an immature appearance. CD19(+) B cells increased 2- to 5-fold in the peripheral blood, 2-fold in the spleen, and 10-fold in the lymph nodes of transgenic mice, whereas CD4(+) T lymphocytes increased 2-fold in both blood and spleen. High serum levels of the cytokines IL-2, IL-4, IL-5, granulocyte colony-stimulating factor, eotaxin, and interferon gamma were observed. Consistent with B-lymphocyte increases, serum immunoglobulin (Ig) M, IgG, and IgE were significantly elevated. Antigenic challenge of the transgenic mice with keyhole limpet hemocyanin (KLH) resulted in a decrease in anti-KLH IgG accompanied by increases of anti-KLH IgA and IgE. In situ hybridization of transgenic tissues revealed that IL-17Rh1 (IL-17BR/Evi27), a receptor that binds IL-17E, is up-regulated. Taken together, these data indicate that IL-17E regulates hematopoietic and immune functions, stimulating the development of eosinophils and B lymphocytes. The fact that hIL-17E overexpression results in high levels of circulating eosinophils, IL-4, IL-5, eotaxin, and IgE suggests that IL-17E may be a proinflammatory cytokine favoring Th2-type immune responses.

• Parrish-Novak J et al.
• Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.
• Nature. 2000; 408: 57-63
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• Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.

• Gauchat JF et al.
• A novel 4-kb interleukin-13 receptor alpha mRNA expressed in human B, T, and endothelial cells encoding an alternate type-II interleukin-4/interleukin-13 receptor.
• Eur J Immunol. 1997; 27: 971-8
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• A 4 kb human interleukin-13 receptor (IL-13R) chain cDNA was cloned from a B cell cDNA library using expressed sequence tags homologous to mouse IL-13R as probes. The deduced protein sequence shows a significant level of sequence identity with the IL-5R and the human IL-13R identified recently by expression cloning. The cytoplasmic region is very highly conserved between human and mouse homologs and contains a consensus binding motif for a signal transducer and activator of transcription. The cDNA encodes a protein binding IL-13 when expressed alone which participates in a receptor complex for both IL-4 and IL-13 when expressed in conjunction with the IL-4R alpha chain. Transcripts for this IL-13R chain could be detected in most tissues and organs studied and in T, B, endothelial cells, basophilic, immature mast cell, and monocytic cell lines. The pattern of expression is different from the other recently cloned IL-13R molecule, and correlates with sites where IL-4 and IL-13 signaling is known to occur. This novel receptor is therefore likely to be implicated in reactions involved in IgE responses, T helper 2 differentiation, adhesion of leukocytes to endothelium, and therefore in pathological phenomena such as allergy, atopy, and asthma.

• Bost KL et al.
• Reverse transcriptase-polymerase chain reaction amplification and partial sequence of T helper 1- and T helper 2-type lymphokine genes from the owl monkey (Aotus trivirgatus).
• Am J Trop Med Hyg. 1997; 56: 351-8
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• The reverse transcriptase-polymerase chain reaction (RT-PCR) was used to amplify selected lymphokine mRNAs from phytohemagglutinin-activated leukocytes of the owl monkey (Aotus trivirgatus). Interleukin-2 (IL-2), IL-4, IL-13, and interferon-gamma were selected as lymphokine mRNAs of interest, since expression of these cytokines helps define the type of T helper lymphocyte response (i.e., TH1 versus TH2). Because sequences for these lymphokine genes were not available for the owl monkey, multiple PCR primers for each lymphokine gene were designed based on published human sequences. Various PCR primer pairs were then used in the RT-PCR to determine the conditions for optimal amplification of each owl monkey cytokine mRNA. In addition, each PCR primer pair was compared for the ability to amplify lymphokine mRNAs from other primate species, including African green (Cercopithecus aethiops), squirrel (Saimiri sciureus), and rhesus (Macaca mulatta) monkeys. The specificity and sensitivity of optimal primer pair was also demonstrated by amplification of as little as 10 fg of each lymphokine gene in a background of 300 ng of irrelevant cDNA. Finally, partial sequences of owl monkey coding regions for IL-2, IL-13, and interferon-gamma were determined and compared for homology with their human counterparts. Together, these studies define specific and sensitive conditions for detection of lymphokine mRNA expression in the owl monkey and provide partial sequence information of the coding region for these lymphokines. This investigation should provide molecular probes to investigate the immune response against malaria and the effectiveness of malaria vaccines in the owl monkey that models this human disease.

• Fossiez F et al.
• T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.
• J Exp Med. 1996; 183: 2593-603
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• Analysis of the cDNA encoding murine interleukin (IL) 17 (cytotoxic T lymphocyte associated antigen 8) predicted a secreted protein sharing 57% amino acid identity with the protein predicted from ORF13, an open reading frame of Herpesvirus saimiri. Here we report on the cloning of human IL-17 (hIL-17), the human counterpart of murine IL-17. hIL-17 is a glycoprotein of 155 amino acids secreted as an homodimer by activated memory CD4+ T cells. Although devoid of direct effects on cells of hematopoietic origin, hIL-17 and the product of its viral counterpart, ORF13, stimulate epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, and granulocyte-colony-stimulating factor, as well as prostaglandin E2. Furthermore, when cultured in the presence of hIL-17, fibroblasts could sustain the proliferation of CD34+ hematopoietic progenitors and their preferential maturation into neutrophils. These observations suggest that hIL-17 may constitute (a) an early initiator of the T cell-dependent inflammmatory reaction; and (b) an element of the cytokine network that bridges the immune system to hematopoiesis.

• Yao Z et al.
• Human IL-17: a novel cytokine derived from T cells.
• J Immunol. 1995; 155: 5483-6
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• A cDNA encoding human IL-17 (hIL-17) was cloned from a CD4+ T cell library. The predicted 155-amino acids sequence contains an N-terminal signal peptide and exhibits 72% amino acid identity with HVS13, an open reading frame from a T-lymphotropic Herpesvirus saimiri, and 63% with murine CTLA8. High levels of hIL-17 were induced from primary peripheral blood CD4+ T cells upon stimulation. When expressed in CV1/EBNA cells, recombinant hIL-17 was secreted in both glycosylated and nonglycosylated forms. A hIL-17.Fc fusion protein and supernatants from cells transfected with hIL-17 induced IL-6 and IL-8 production and enhanced the surface expression of the intracellular adhesion molecule-1 (ICAM-1) in human fibroblasts.

• Burton JD et al.
• A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells.
• Proc Natl Acad Sci U S A. 1994; 91: 4935-9
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• In early phases of human T-cell lymphotrophic virus I-induced adult T-cell leukemia (ATL), the malignant cell proliferation is associated with an autocrine process involving coordinate expression of interleukin (IL) 2 and its receptor. However, during late-phase ATL, leukemic cells no longer produce IL-2 yet continue to express high-affinity IL-2 receptors. During studies to define pathogenic mechanisms that underlie this IL-2-independent proliferation, we demonstrated that the ATL cell line HuT-102 secretes a lymphokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Conditioned medium from HuT-102, when added to the IL-2-dependent CTLL-2 line, yielded a stimulation index of 230. Since CTLL-2 was purported to be IL-2-specific, we performed a number of studies to exclude IL-2 production by HuT-102. Stimulation of CTLL-2 cells by HuT-102-conditioned medium was not meaningfully inhibited by addition of an antiserum to IL-2. Furthermore, uninduced HuT-102 cells did not express mRNA encoding IL-2 as assessed by Northern blot analysis. No biological activity on CTLL-2 cells was mediated by purified IL-1, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, or granulocyte/macrophage colony-stimulating factor, thus differentiating these factors from IL-T. Based on preliminary biochemical data, IL-T is a protein with a pI value of 4.5 and a molecular mass in SDS gels of 14 kDa. In addition to its action on CTLL-2 cells, 3200-fold-purified IL-T stimulated proliferation of the human cytokine-dependent T-cell line Kit-225. Furthermore, addition of IL-T enhanced cytotoxic activity of large granular lymphocytes (i.e., induced lymphokine-activated killer cells). Thus, IL-T is a lymphokine that plays a role in T-cell proliferation and induction of lymphokine-activated killer cells. Furthermore, IL-T may contribute to IL-2-independent proliferation of select ATL cells and lines.

• Zurawski G, de Vries JE
• Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells.
• Immunol Today. 1994; 15: 19-26
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• Interleukin 13 (IL-13) is a recently described protein secreted by activated T cells which is a potent in vitro modulator of human monocyte and B-cell functions. The data, reviewed here by Gerard Zurawski and Jan de Vries, shows that IL-13 shares biological activities with IL-4, their genes are closely linked in both the human and mouse genomes, and there is sequence homology between IL-13 and IL-4 proteins. Although the cloned IL-4 receptor protein (IL-4R) does not bind IL-13, it appears that the functional IL-4R and IL-13R share a common subunit that is important for signal transduction.

• Grabstein KH et al.
• Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor.
• Science. 1994; 264: 965-8
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• A cytokine was identified that stimulated the proliferation of T lymphocytes, and a complementary DNA clone encoding this new T cell growth factor was isolated. The cytokine, designated interleukin-15 (IL-15), is produced by a wide variety of cells and tissues and shares many biological properties with IL-2. Monoclonal antibodies to the beta chain of the IL-2 receptor inhibited the biological activity of IL-15, and IL-15 competed for binding with IL-2, indicating that IL-15 uses components of the IL-2 receptor.

• Kozlow EJ, Wilson GL, Fox CH, Kehrl JH
• Subtractive cDNA cloning of a novel member of the Ig gene superfamily expressed at high levels in activated B lymphocytes.
• Blood. 1993; 81: 454-61
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• Using subtractive cDNA cloning we have isolated a series of cDNA clones that are exclusively or selectively expressed in B lymphocytes. mRNA transcripts from one such cDNA clone, referred to as BL11, were found to be expressed at low levels in RNA from normal B lymphocytes, but at very high levels in RNA from in vitro activated B lymphocytes. One major 2.5-kb BL11 mRNA transcript was detected, while low levels of 4.8-, 1.8-, and 1.6-kb transcripts were also found. BL11 mRNA transcripts were absent or present at low levels in RNA prepared from resting or mitogen activated T cells, a variety of lymphoid cell lines including several B-cell lines, and several different tissues. Low levels of BL11 transcripts were found in poly(A) RNA purified from brain and lung. A study of the kinetics of BL11 mRNA accumulation in B lymphocytes stimulated in vitro with Staphylococcus aureus Cowan strain I showed a rapid induction of BL11 mRNA within 2 hours of stimulation with peak expression by 16 hours and a mild decrease with time following the peak levels. Consistent with the in vitro data, in situ hybridization using antisense BL11 RNA probes and human tonsillar tissue localized BL11 transcripts in B-cell-enriched areas. Multiple BL11 cDNA and genomic clones were isolated and sequenced to complete and verify the BL11 cDNA sequence (2,404 bp). A 615-nucleotide open reading frame predicted to encode for a 205-amino acid protein with a molecular weight of 23 Kd was identified. Search of protein data bases with the predicted BL11 protein showed homologies to several members of the Ig superfamily. Analysis of the predicted protein showed a likely signal peptide, a single membrane spanning region, and one V-like Ig domain with three predicted n-glycosylation sites. Southern blot analysis of human genomic DNA suggested that BL11 is a single copy gene without evidence of rearrangement. Primer extension and S1 nuclease mapping identified four tightly clustered transcriptional start sites approximately 40 bp upstream of the predicted translation start site. The first 270 bp of the promoter region were sequenced and found to contain a CATAA box rather than a TATAA box and several DNA motifs found in activation genes. BL11 should prove to be an interesting gene that likely encodes for a protein involved in B-cell activation.

• McKenzie AN et al.
• Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function.
• Proc Natl Acad Sci U S A. 1993; 90: 3735-9
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• We have isolated the human cDNA homologue of a mouse helper T-cell-specific cDNA sequence, called P600, from an activated human T-cell cDNA library. The human cDNA encodes a secreted, mainly unglycosylated, protein with a relative molecular mass of approximately 10,000. We show that the human and mouse proteins cause extensive morphological changes to human monocytes with an associated up-regulation of major histocompatibility complex class II antigens and the low-affinity receptor for immunoglobulin E (Fc epsilon RII or CD23). In addition, they stimulate proliferation of human B cells that have been activated by anti-IgM antibodies or by anti-CD40 monoclonal antibodies presented by a mouse Ltk- cell line transfected with CDw32. Furthermore, the human protein induced considerable levels of IgM and IgG, but no IgA production, in cultures in which highly purified human surface IgD+ or total B cells were cocultured with an activated CD4+ T-cell clone. Based on these findings, we propose that this immunoregulatory protein be designated interleukin 13.

• Berezowicz PS
• [Interleukins 4 and 5--factors regulating the activity of the immune system]
• Postepy Hig Med Dosw. 1991; 45: 17-44

• Harriman GR, Strober W
• The immunobiology of interleukin-5.
• Year Immunol. 1989; 5: 160-77

• Fuller GM, Grenett HE
• The structure and function of the mouse hepatocyte stimulating factor.
• Ann N Y Acad Sci. 1989; 557: 31-44

• Ohara J
• Interleukin-4: molecular structure and biochemical characteristics, biological function, and receptor expression.
• Year Immunol. 1989; 5: 126-59

• Mita S, Takatsu K
• [Cytokines and receptors--their functions, structures and cloning of code genes. TRF/IL-5 and receptor]
• Nippon Rinsho. 1988; 46: 1023-8

• Noma T, Honjo T
• [Cytokines and receptors--their functions, structures and cloning of code genes. Interleukin-4]
• Nippon Rinsho. 1988; 46: 1014-22

• Sideras P, Noma T, Honjo T
• Structure and function of interleukin 4 and 5.
• Immunol Rev. 1988; 102: 189-212

• Matsuda T, Hirano T, Kishimoto T
• [B-cell stimulating factor, BSF-2 and autoimmune diseases]
• Nippon Rinsho. 1988; 46: 749-54

• Kishimoto T
• [Cytokines--DNA to immunologic diseases]
• Nippon Rinsho. 1988; 46: 981-3

• Arai N et al.
• Molecular biology of T cell-derived lymphokines: structure and biology of interleukin 4.
• Dev Biol Stand. 1988; 69: 57-63

• Russmann E
• BCGFLMW-sensitivity of human B-cell lines in the MTT-cleavage assay.
• Dev Biol Stand. 1988; 69: 75-8

• Wong GG, Clark SC
• Multiple actions of interleukin 6 within a cytokine network.
• Immunol Today. 1988; 9: 137-9

• Namen AE et al.
• Stimulation of B-cell progenitors by cloned murine interleukin-7.
• Nature. 1988; 333: 571-3
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• The events involved in the commitment and development of lymphoid lineage cells are poorly understood. We have used a recently described long-term culture system to establish a bioassay that can detect a novel growth factor capable of stimulating the proliferation of lymphoid progenitors. Using direct expression in mammalian cells we have isolated a complementary DNA clone encoding this novel haematopoietic growth factor, designated interleukin-7.

• Kishimoto T, Hirano T
• A new interleukin with pleiotropic activities.
• Bioessays. 1988; 9: 11-5

• Sanderson CJ, Campbell HD, Young IG
• Molecular and cellular biology of eosinophil differentiation factor (interleukin-5) and its effects on human and mouse B cells.
• Immunol Rev. 1988; 102: 29-50

• Matsuda T, Hirano T
• [Pleiotropic functions of BSF-2/IL-6]
• Tanpakushitsu Kakusan Koso. 1988; 33: 1317-22

• Hirano T et al.
• [Cytokines and receptors--their functions, structures and cloning of code genes. Functional polymorphism of BSF-2/IL-6 and its abnormal expression]
• Nippon Rinsho. 1988; 46: 1029-35

• Kishimoto T, Hirano T
• Molecular regulation of B lymphocyte response.
• Annu Rev Immunol. 1988; 6: 485-512

• Honjo T et al.
• Structure and function of interleukins 4 and 5.
• Acta Paediatr Jpn. 1987; 29: 546-51

• Yaoita Y
• [Structure and function of B cell growth factors]
• Tanpakushitsu Kakusan Koso. 1987; 32: 1568-71