No abstract

We report here the cloning and characterization of four new members of the interleukin-1 (IL-1) family (FIL1␦, FIL1⑀, FIL1, and FIL1, with FIL1 standing for "Family of IL-1"). The novel genes demonstrate significant sequence similarity to IL-1␣, IL-1␤, IL-1ra, and IL-18, and in addition maintain a conserved exon-intron arrangement that is shared with the previously known members of the family. Protein structure modeling also suggests that the FIL1 genes are related to IL-1␤ and IL-1ra. The novel genes form a cluster with the IL-1s on the long arm of human chromosome 2.The cytokine interleukin-1 (IL-1) 1 elicits a wide array of biological activities that initiate and promote the host response to injury or infection, including fever, sleep, loss of appetite, acute phase protein synthesis, chemokine production, adhesion molecule up-regulation, vasodilatation, the pro-coagulant state, increased hematopoiesis, and production and release of matrix metalloproteinases and growth factors (1). It does so by activating a set of transcription factors that includes NFB and AP-1, which in turn promote production of effectors of the inflammatory response, such as the inducible forms of cycloxygenase and nitric oxide synthase (2, 3). Interleukin 1 activity actually resides in each of two molecules, IL-1␣ and IL-1␤, which act by binding to a common receptor composed of a ligand binding chain, the type I IL-1 receptor, and a required signaling component, the IL-1R accessory protein (AcP) (4 -7). A third member of the family, the IL-1 receptor antagonist (IL-1ra), also binds to the type I IL-1 receptor but fails to bring about the subsequent interaction with AcP, thus not only not signaling itself but also, by blocking the receptor, preventing the action of the agonist IL-1s (8, 9). Additional regulation is provided by the type II, or decoy, IL-1 receptor, which binds and sequesters the agonist IL-1s (especially IL-1␤) without inducing any signaling response of its own (10 -13). The two agonist IL-1s (IL-1␣ and IL-1␤) are synthesized as larger precursors which undergo proteolytic removal of their pro-domains to generate the mature cytokines (14). At least for IL-1␤, this processing is coupled to secretion (15, 16). IL-1ra, in contrast, contains a signal peptide and is secreted by the more traditional route through the endoplasmic reticulum (9).Recently, another cytokine, interleukin 18 (17, 18) was recognized to be related to the interleukin-1 family based on the similarity of its amino acid sequence and predicted tertiary structure (19). IL-18 induces the production of ␥-interferon from T cells, especially in combination with IL-12, and stimulates the killing activity of cytotoxic T lymphocytes and NK cells by . Like the agonist IL-1s, IL-18 contains a prodomain that is removed by the same protease, caspase-1, that processes IL-1␤ (21, 22). Consistent with its being related to the IL-1s, IL-18 binds a receptor which is homologous to the IL-1 receptor. The ligand-binding chain IL1Rrp1 (or IL-18R␣) (23, 24) was cloned initially on ...

Using a bioassay consisting of the proliferation of a murine B cell line, a cDNA of a gene whose product supports the growth of that cell line was isolated from a thymic stromal cell line. This factor, termed thymic stromal lymphopoietin (TSLP), is a protein of 140 amino acids. The gene encoding TSLP was mapped to murine chromosome 18. Purified recombinant TSLP supported the growth of pre-B cell colonies in vitro, but had no myelopoietic activity. TSLP had comitogenic activity for fetal thymocytes, but was not as potent as interleukin 7 in lobe submersion cultures. Injection of TSLP into neonatal mice induced the expansion of B220+BP-1+ pre-B cells.

The cellular receptor for murine thymic stromal lymphopoietin (TSLP) was detected in a variety of murine, but not human myelomonocytic cell lines by radioligand binding. cDNA clones encoding the receptor were isolated from a murine T helper cell cDNA library. TSLP receptor (TSLPR) is a member of the hematopoietin receptor family. Transfection of TSLPR cDNA resulted in only low affinity binding. Cotransfection of the interleukin 7 (IL-7)Rα chain cDNA resulted in conversion to high affinity binding. TSLP did not activate cells from IL-7Rα−/− mice, but did activate cells from γc−/− mice. Thus, the functional TSLPR requires the IL-7Rα chain, but not the γc chain for signaling.

No abstract