Evidence for an intracellular activation loop in the IL-1 system.
The mechanism of action of the pleiotropic cytokine interleukin-1 (IL-1) is only incompletely understood. A unique feature among cytokines is its internalization and translocation to the nuclear area in nondegraded form, suggesting intracellular activities of the molecule. To define activities of that kind, a pair of IL-1 receptor type I (IL-1RI)-positive EL4 thymoma cells with differential receptor functionality was transfected with plasmids which caused intracellular expression of FLAGIL-1 alpha fusion peptides. Intracellular delivery of IL-1 costimulated expression of IL-2 mRNA and production of IL-2 protein. This effect was not mediated by the plasma membrane IL-1RI. The cells were permanently activated, and in cells with functional IL-1RI, appearance of membrane IL-1RI was abrogated. Thus, intracellularly delivered IL-1 can bypass and replace the plasma membrane IL-1RI, possibly via an as yet undefined intracellular receptor. This is a new modality of IL-1 action and suggests a role for the intracellular IL-1R antagonists (icIL-IRa).
Hofmeister
R
R
Department of Internal Medicine I, University of Regensburg, Germany.
Männel
D N
DN
Falk
W
W
D002462:Cell Membrane / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D015870:Gene Expression; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D009842:Oligopeptides; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D015347:RNA Probes / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D012795:Sialoglycoproteins / Q000378:metabolism; D013945:Thymoma / Q000378:metabolism*; D013953:Thymus Neoplasms / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007376:Interleukin-2; D009842:Oligopeptides; D010455:Peptides; D015347:RNA Probes; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D012795:Sialoglycoproteins; C085706:FLAG peptide