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Identification and Initial Characterization of Four Novel Members of the Interleukin-1 Family*

Open AccessPublished:April 07, 2000DOI:https://doi.org/10.1074/jbc.275.14.10308
      Interleukin-1 (IL-1), fibroblast growth factors (FGFs), and their homologues are secreted factors that share a common β-barrel structure and act on target cells by binding to cell surface receptors with immunoglobulin-like folds in their extracellular domain. While numerous members of the FGF family have been discovered, the IL-1 family has remained small and outnumbered by IL-1 receptor homologues. From expressed sequence tag data base searches, we have now identified four additional IL-1 homologues, IL-1H1, IL-1H2, IL-1H3, and IL-1H4. Like most other IL-1/FGFs, these proteins do not contain a hydrophobic leader sequence. IL-1H4 has a propeptide sequence, while IL-1H1, IL-1H2, and IL-1H3 encode only the mature protein. Circular dichroism spectra and thermal stability analysis suggest that IL-1H1 folds similarly to IL-1ra. The novel homologues are not widely expressed in mammals. IL-1H1 is constitutively expressed only in placenta and the squamous epithelium of the esophagus. However, IL-1H1 could be inducedin vitro in keratinocytes by interferon-γ and tumor necrosis factor-α and in vivo via a contact hypersensitivity reaction or herpes simplex virus infection. This suggests that IL-1H1 may be involved in pathogenesis of immune mediated disease processes. The addition of four novel IL-1 homologues suggests that the IL-1 family is significantly larger than previously thought.
      IL
      interleukin
      IL-1H
      IL-1 homologue
      IL-1R
      IL-1 receptor
      TNF
      tumor necrosis factor
      IFN
      interferon
      CHS
      contact hypersensitivity
      HSV
      herpes simplex virus
      GAPDH
      glyceraldehyde-3-phosphate dehydrogenase
      PBS
      phosphate-buffered saline
      FGF
      fibroblast growth factor
      EST
      expressed sequence tag
      The interleukin (IL)1-1/fibroblast growth factor (FGF) family is a growing family of proteins that share a common β-barrel structure consisting of 12 β-strands (
      • Priestle J.P.
      • Schaer H.P.
      • Gruetter M.G.
      ,
      • Zhu X.
      • Komiya H.
      • Chirino A.
      • Faham S.
      • Fox G.M.
      • Arakawa T.
      • Hsu B.T.
      • Rees D.C.
      ,
      • Vigers G.P.A.
      • Anderson L.J.
      • Caffes P.
      • Brandhuber B.J.
      ,
      • Schreuder H.
      • Tardif C.
      • Trump-Kallmeyer S.
      • Soffientini A., E., S.
      • Akeson A.
      • Bowlin T.
      • Yanofsky S.
      • Barrett R.W.
      ). There are currently 19 members of the FGF family (FGF1–19) (
      • Xu X.L.
      • Weinstein M.
      • Li C.L.
      • Deng C.X.
      ,
      • Nishimura T.
      • Utsunomiya Y.
      • Hoshikawa M.
      • Ohuchi H.
      • Itoh N.
      ,
      • Ohbayashi N.
      • Hoshikawa M.
      • Kimura S.
      • Yamasaki M.
      • Fukui S.
      • Itoh N.
      ) and four members of the IL-1 family (IL-1α, IL-1β, IL-1ra, and IL-18) (
      • Dinarello C.A.
      ,
      • Dinarello C.A.
      • Novick D.
      • Puren A.J.
      • Fantuzzi G.
      • Shapiro L.
      • Muhl H.
      • Yoon D.Y.
      ). With a few exceptions, most IL-1/FGFs are synthesized as intracellular proteins without a characteristic hydrophobic leader peptide but nevertheless are released from cells and act on target cells by binding and signaling through cell surface receptors. In some cases, such as IL-1β and IL-18, proteolytic cleavage of a precursor form of the protein is required for elaboration of the active form of the ligand (
      • Hazuda D.
      • Webb R.L.
      • Simon P.
      • Young P.
      ,
      • Cerretti D.P.
      • Kozlosky C.J.
      • Mosley B.
      • Nelson N.
      • Van Ness K.
      • Greenstreet T.A.
      • March C.J.
      • Kronheim S.R.
      • Druck T.
      • Cannizzaro L.A.
      • Huebner K.
      • Black R.A.
      ,
      • Thornberry N.A.
      • Bull H.G.
      • Calaycay J.R.
      • Chapman K.T.
      • Howard A.D.
      • Kostura M.J.
      • Miller D.K.
      • Molineaux S.M.
      • Weidner J.R.
      • Aunins J.
      • Elliston K.O.
      • Ayala J.M.
      • Casano F.J.
      • Chin J.
      • Ding G.J.-F.
      • Egger L.A.
      • Gaffney E.P.
      • Limjuco G.
      • Palyha O.C.
      • Raju S.M.
      • Rolando A.M.
      • Salley J.P.
      • Yamin T.-T.
      • Lee T.D.
      • Shively J.E.
      • MacCross M.
      • Mumford R.A.
      • Schmidt J.A.
      • Tocci M.J.
      ,
      • Gu Y.
      • Kuida K.
      • Tsutsui H.
      • Ku G.
      • Hsiao K.
      • Fleming M.A.
      • Hayashi N.
      • Higashino K.
      • Okamura H.
      • Nakanishi K.
      • Kurimoto M.
      • Tanimoto T.
      • Flavell R.A.
      • Sato V.
      • Harding M.W.
      • Livingston D.J.
      • Su M.S.-S.
      ). The IL-1 and FGF receptors also share structural homology in their extracellular ligand binding domain, since they both consist of multiple immunoglobulin-like repeats (
      • Vigers G.P.A.
      • Anderson L.J.
      • Caffes P.
      • Brandhuber B.J.
      ,
      • Schreuder H.
      • Tardif C.
      • Trump-Kallmeyer S.
      • Soffientini A., E., S.
      • Akeson A.
      • Bowlin T.
      • Yanofsky S.
      • Barrett R.W.
      ,
      • Zhang Y.
      • Gorry M.C.
      • Post J.C.
      • Ehrlich G.D.
      ), and this appears to lead to a similar mode of ligand recognition (
      • Plotnikov A.N.
      • Schlessinger J.
      • Hubbard S.R.
      • Mohammadi M.
      ).
      While the overall folds of the ligands and receptor extracellular domains have been maintained evolutionarily, the family has evolved into two distinct arms, the IL-1s and the FGFs, which show no significant sequence homology and have distinct biological properties. The limited sequence homology is also seen between IL-1 family members and results from the small number of internal residues required to maintain the β-barrel structure and the extensive use of backbone elements in receptor recognition (
      • Vigers G.P.A.
      • Anderson L.J.
      • Caffes P.
      • Brandhuber B.J.
      ,
      • Schreuder H.
      • Tardif C.
      • Trump-Kallmeyer S.
      • Soffientini A., E., S.
      • Akeson A.
      • Bowlin T.
      • Yanofsky S.
      • Barrett R.W.
      ). The distinction in biological activities reflects differences in the intracellular regions of their cognate receptors. The FGF receptors encode a tyrosine kinase within the intracellular domain that is stimulated upon ligand binding and initiates a signaling cascade that results in cell proliferation. This contributes to their role in stimulating tissue growth during development and repair. In contrast, the IL-1 receptors do not encode any enzymatic activity in their intracellular domains, but upon ligand binding, they recruit two serine/threonine protein kinases, the interleukin-1 receptor-associated kinases, through motifs shared with the highly evolutionarily conserved toll receptor family (
      • Rock F.L.
      • Hardiman G.
      • Timans J.C.
      • Kastelein R.A.
      • Bazan J.F.
      ). These stimulate intracellular signaling pathways, leading to the activation of NF-κB and AP-1 transcription factors (
      • O'Neill L.A.
      • Greene C.
      ,
      • Auron P.E.
      ) that in turn induce genes involved in the initiation of immune and inflammatory responses. Thus, IL-1α and -β stimulate the production of chemokines, cytokines, and adhesion molecules that serve to recruit leukocytes to sites of infection or injury and initiate an inflammatory response. IL-18 stimulates the production of TH1 helper T cells resulting in a cell-mediated immune response that can lead to cancer immunity and delayed type hypersensitivity responses (
      • Okamura H.
      • Tsutsui H.
      • Komatsu T.
      • Yutsudo M.
      • Hakura A.
      • Tanimoto T.
      • Torigoe K.
      • Okura T.
      • Nukuda Y.
      • Hattori K.
      • Akita K.
      • Namba M.
      • Tanabe F.
      • Konishi K.
      • Fukuda S.
      • Kurimoto M.
      ).
      IL-1s activate their target receptors by bringing together two different receptor subunits. IL-1α and IL-1β bind with subnanomolar affinity to the cell surface type I IL-1R and recruit IL-1R accessory protein in order to stimulate target cells (
      • O'Neill L.A.
      • Greene C.
      ). Similarly, IL-18 binds to the IL-18 receptor (IL1rrp) with 20 nm affinity and recruits the IL-18R accessory protein (
      • Torigoe K.
      • Ushio S.
      • Okura T.
      • Kobayashi S.
      • Taniai M.
      • Kunikata T.
      • Murakami T.
      • Sanou O.
      • Kojima H.
      • Fujii M.
      • Ohta T.
      • Ikeda M.
      • Ikegami H.
      • Kurimoto M.
      ,
      • Born T.L.
      • Thomassen E.
      • Bird T.A.
      • Sims J.E.
      ). The activity of both IL-1 and IL-18 is modulated by the soluble or membrane-bound decoy receptors, IL-1R type II and IL-18BP, respectively (
      • McMahan C.J.
      • Slack J.L.
      • Mosley B.
      • Cosman D.
      • Lupton S.D.
      • Brunton L.L.
      • Grubin C.E.
      • Wignall J.M.
      • Jenkins N.A.
      • Brannan C.I.
      • Copeland N.G.
      • Huebner K.
      • Croce C.M.
      • Cannizzaro L.A.
      • Benjamin D.
      • Dower S.K.
      • Spriggs M.K.
      • Sims J.E.
      ,
      • Novick D.
      • Kim S.H.
      • Fantuzzi G.
      • Reznikov L.L.
      • Dinarello C.A.
      • Rubinstein M.
      ). IL-1 activity is also moderated by the presence of a natural receptor antagonist, IL-1ra, which binds to the type I IL-1R but does not recruit IL-1RAcP. However, there are some IL-1R-like receptors that have yet to be paired with ligands, such as ST2/T1 and IL-1rrp2 (
      • Tominaga S.
      ,
      • Klemenz R.
      • Hoffmann S.
      • Werenskiold A.K.
      ,
      • Kumar S.
      • Minnich M.D.
      • Young P.R.
      ,
      • Lovenberg T.W.
      • Crowe P.D.
      • Liu C.L.
      • Chalmers D.T.
      • Liu X.J.
      • Liaw C.
      • Clevenger W.
      • Oltersdorf T.
      • Desouza E.B.
      • Maki R.A.
      ). This suggests that there may be additional members of the IL-1 family. In this paper, we describe the discovery of four novel members of the IL-1 family and the initial biological and biochemical characterization of IL-1H1.

      Acknowledgments

      We thank Annalisa Hand, Cheng Zou, and Jim Alston for expert technical assistance; Genetic Technologies for nucleotide synthesis and DNA sequencing; Wendy Crowell for preparation of the figures; and Drs. Maxine Gowen, John Lee, Lisa Marshall, and Michael Lotze for support and critical reading of the manuscript.

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