title: Autocrine interleukin-1 receptor antagonist can support malignant growth of glioblastoma by blocking growth-inhibiting autocrine loop of interleukin-1.
abstract: In situ hybridization (ISH) of human glioblastoma tissue sections revealed expression of interleukin-1 (IL-1)alpha and/or beta and IL-1 receptor types I and II (IL-1R I and II) in the majority of cases evaluable. To understand the function of IL-1-family members in human glioblastomas, we have studied 6 glioblastoma cell lines. RT-PCR, ISH, ELISA and 125I-IL-1-binding assays revealed expression of IL-1 and high-affinity receptors for human (h)IL-1 in all but 1 cell line. Using a colony growth assay in semi-solid media for testing serial plating efficacy (PE, number of colonies per number of cells seeded in %), only the IL-1R-negative cell line was not influenced by recombinant human (rh)IL-1alpha or -beta, whereas IL-1 down-regulated the self-renewal of clonogenic cells of the other glioblastomas. Tritiated thymidine uptake was down-regulated by rhIL-1 in all cell lines studied. Cell viability remained unchanged by rhIL-1. Wherever growth modulation by rhIL-1 was detected, it could be reversed by either soluble IL-1R I or II or by rhIL-1 receptor antagonist (ra). IL-1ra not only was able to reverse rhIL-1-induced growth modulation but alone could modulate glioblastoma growth in comparison with control in cell lines producing IL-1. Our results show the presence of public autocrine loops for IL-1 leading to growth inhibition in some glioblastomas. To understand these loops, we have studied expression and function of IL-1ra in glioblastomas. ISH of human glioblastoma tissue sections revealed expression of hIL-1ra in all 8 cases evaluable. In 4 of 6 cell lines, IL-1ra was found in the supernatant under constitutive conditions, the IL-1R-negative line being among the 2 non-producers. The other non-producing cell line, HTB 17, showed expression of hIL-1R II. Most interestingly, a neutralizing antibody against IL-1ra down-regulated growth of IL-1- and IL-1ra-producing glioblastoma cells to approx. 30% of the controls. Thus, public autocrine loops for IL-1 in human glioblastomas exist and result in growth inhibition. An autocrine production of IL-1-antagonizing molecules such as IL-1ra by these tumors can counteract this IL-1 function and represent a basic escape mechanism supporting malignant growth in some glioblastomas.
authors.affiliation: Department of Hematology/Oncology, Benjamin Franklin Hospital, Freie Universitat Berlin, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Oelmann
authors.forename: A
authors.initials: A
authors.lastname: Kraemer
authors.forename: H
authors.initials: H
authors.lastname: Serve
authors.forename: B
authors.initials: B
authors.lastname: Reufi
authors.forename: D
authors.initials: D
authors.lastname: Oberberg
authors.forename: S
authors.initials: S
authors.lastname: Patt
authors.forename: H
authors.initials: H
authors.lastname: Herbst
authors.forename: H
authors.initials: H
authors.lastname: Stein
authors.forename: E
authors.initials: E
authors.lastname: Thiel
authors.forename: W E
authors.initials: WE
authors.lastname: Berdel
mesh_terms: D001665:Binding Sites; D001932:Brain Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D012795:Sialoglycoproteins / Q000502:physiology*; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D013936:Thymidine