Disease relevance of Il1rl1

• In addition, T(3) downregulated the expression of T1, a gene that is overexpressed in human breast adenocarcinomas and is induced by mitogens, serum, and several oncogenes and cytokines [1].
• Using a primary pulmonary granuloma model, induced with Schistosoma mansoni eggs, we demonstrate that granuloma formation, characterized by eosinophil infiltration, is abrogated in T1/ST2-deficient mice [2].
• Within this sequence there is a 12-O-tetradecanoylphorbol 13-acetate (TPA)-responsive element (TRE) which is essential for T1 promoter induction in response to the forced expression of the transcription factor AP-1 in NIH 3T3 fibroblasts and F9 teratocarcinoma cells [3].
• In contrast, allogeneic T2 cells expanded less and maintained T2 secretion but did not develop significant allospecificity.Allogeneic, but not syngeneic, T1 cells mediated a GVT effect against host-type breast cancer cells, as median survival time (MST) increased from 25.6 +/- 2.6 (tumor controls) to 69.2 +/- 5.9 days (P < 1.2 x 10(-9)) [4].
• ST2, an IL-1R family member, attenuates inflammation and lethality after intestinal ischemia and reperfusion [5].

High impact information on Il1rl1

• ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance [6].
• ST2 is a member of the TIR family that does not activate NF-kappa B and has been suggested as an important effector molecule of T helper type 2 (T(H)2) responses [6].
• Monoclonal anti-T1/ST2 treatment reduced lung inflammation and the severity of illness in mice with Th2 (but not Th1) immunopathology [7].
• T1/ST2 was present on a subset of CD4(+) cells from mice with eosinophilic lung disease [7].
• T1/ST2 is also expressed on mast cells, which are critical for Th2-mediated effector responses [8].

Chemical compound and disease context of Il1rl1

• In an acute lung injury model, protein and mRNA expression levels of ST2 increased to the maximal level at 24-72h after the LPS challenge [9].
• Proton NMR longitudinal relaxation times (T1; 10.7 MHz; 37 degrees C) were measured in the kidneys and blood serum of mice inoculated with P388 leukemia, and/or treated with the chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-Pt) [10].

Biological context of Il1rl1

• T1 is a c-Fos- and FosB-responsive gene which is induced by growth factors through multiple signal transduction pathways [11].
• Proliferating cells continued to express T1 mRNA at a lower level, whereas growth arrest induced either by serum deprivation or by contact inhibition was paralleled by the disappearance of the T1 mRNA [11].
• Nucleotide sequence analysis of the cloned ST2L cDNA revealed that it had an open reading frame encoding a polypeptide of 567 amino acids [12].
• Thus, ST2 suppresses IL-1R and TLR4 signaling via MyD88- and Mal-dependent pathways and modulates innate immunity [13].
• Point mutations within these sequence motifs reduced basal T1 promoter activity and serum inducibility [3].

Anatomical context of Il1rl1

• 2. We also observed expansion of activated CD3(+)/CD4(+) T cells expressing the T helper-2-associated marker T1/ST2 in the lung, most notably 5 d after challenge [14].
• The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function [8].
• T1/ST2, an orphan receptor with homology with the interleukin (IL)-1 receptor family, is expressed constitutively and stably on the surface of T helper type 2 (Th2) cells, but not on Th1 cells [8].
• ST2/T1 protein functionally binds to two secreted proteins from Balb/c 3T3 and human umbilical vein endothelial cells but does not bind interleukin 1 [15].
• One of these changes in Swiss 3T3 cells is the strong accumulation of T1 mRNA which encodes a secreted glycoprotein of the immunoglobulin superfamily [11].

Associations of Il1rl1 with chemical compounds

• T1/ST2(-/-) mice showed normal Th2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis as well as in the mouse model of allergen-induced airway inflammation [8].
• In the course of studying the ST2 gene, which was initially found to be expressed specifically at the G0/G1 transitional state in BALB/c-3T3 cells and was one of the primary response genes, we found another ST2-related mRNA, designated as ST2L, in serum-stimulated BALB/c-3T3 cells in the presence of cycloheximide [12].
• In contrast, anisomycin induces T1 gene expression at concentrations which block translation completely [16].
• The T1/2 of IL 2 mRNA remained unchanged after alpha MM treatment as compared to actinomycin D treatment, while IL 4 mRNA became labilized after withdrawal of the signal [17].
• Furthermore, pretreatment with ST2 protein significantly reduced the protein production and gene expression of IL-1alpha, IL-6, and TNF-alpha in LPS-stimulated MH-S cells in vitro [9].

Regulatory relationships of Il1rl1

• Here we show that Fit-1 is directly regulated by the estrogen-inducible transcription factor Fos-ER and that it belongs to the family of delayed early genes [18].
• T1/ST2 is a stable cell surface marker selectively expressed on type 2 T helper (Th2) effector cells [19].
• Altogether, our results suggest that FasL-induced tolerance is concomitant with a move away from a T1 type response, and a CD4 T cell-mediated regulation of the allocytotoxic T cell response [20].
• The T1 gene is strongly induced by various mitogens in quiescent NIH3T3 fibroblasts but not in ras transformed NIH3T3 cells [16].
• IL-4 enhances, whereas IFN-gamma suppresses ST2L expression via direct modulation of the distal promoter of the ST2L gene [21].

Other interactions of Il1rl1

• Furthermore, all known inducers of the T1 gene also lead to c-fos gene activation [11].
• The ST2 gene product is highly similar to the extracellular portion of IL-1 receptors type 1 and type 2, and the ST2L gene product shows a marked similarity with entire IL-1 receptor type 1 [12].
• Signaling through the T1/ST2 molecule is not necessary for Th2 differentiation but is important for the regulation of type 1 responses in nonhealing Leishmania major infection [19].
• Surprisingly, even in the presence of an elevated Th1 response, the production of antigen-specific type 2 cytokines was not altered in the group of mice treated with the anti-T1/ST2 MAb or the T1-Fc fusion protein [19].
• This T1-associated GVT effect operated independently of fasL because T1 cells from gld mice mediated tumor-free survival [4].

Analytical, diagnostic and therapeutic context of Il1rl1

• Northern blot analysis with specific 5' and 3' probes directly demonstrated tight coupling between alternative promoter usage and 3' processing of the Fit-1 transcripts [18].
• Using differential display PCR, we have identified a gene encoding a cell membrane bound molecule, originally designated ST2L, T1, DER4, or Fit, expressed constitutively and stably on the surface of murine Th2s, but not Th1s even after stimulation with a range of immunological stimuli [22].
• T1 recipients had moderate GVHD (histologic score, 4 of 12) that contributed to lethality after bone marrow transplantation; in contrast, T2 recipients had minimal GVHD (histologic score, 1 of 12) [4].
• The St2 locus has also been mapped to chromosome 2q11.2, using a human ST2 genomic DNA clone, by in situ hybridization [23].
• Molecular cloning of the murine ST2 gene. Characterization and chromosomal mapping [24].

References