title: Neutrophils process interleukin-1beta and interleukin-18 precursors in a caspase-1-like fashion--processing is inhibited by human vascular smooth muscle cells.
abstract: Inflammation contributes to the pathogenesis of atherosclerosis. Proinflammatory cytokines, including interleukin-1 (IL-1), may be involved in the local inflammation occurring in the vessel wall. Vascular smooth muscle cells express the unprocessed IL-1beta precursor molecule. Invading leukocytes, such as monocytes or polymorphonuclear granulocytes (PMN) may activate the IL-1beta precursor during atherogenesis. Thus, we investigated the capacity of PMN to process IL-1beta and IL-18 precursors. Processing was analyzed using Western blot and bioassay for IL-1-activity was performed. As few as 80 to 400 PMN/mL detectably processed preIL-1beta. PMN also cleaved the caspase-1 substrate preIL-18. The preIL-1beta and preIL-18 cleavage products were located at the same apparent molecular weight as those resulting from cleavage by monocyte-derived caspase-1. PMN expressed caspase-1 mRNA and immunoreactive protein. The N-terminus of the preIL-1beta cleavage product expressed the sequence expected for caspase-1 cleavage. The cleavage product was active in the bioassay for IL-1 activity, and the caspase-1 inhibitor YVAD blocked processing. We have shown previously that SMC can block processing of preIL-1 by caspase-1. In contrast, SMC do not block processing of PARP by caspase-3. Here, we show that SMC also inhibited the PMN-mediated processing of recombinant and native preIL-1beta or preIL-18 depending on the cell number, whereas EC or fibroblasts did not block processing. Our results indicate that PMN can activate preIL-1beta in a caspase-1-like fashion. During inflammatory processes, PMN may activate preIL-1beta released from SMC, thereby altering IL-1-mediated cardiovascular functions, including contractility, apoptosis, and cytokine production.
authors.affiliation: Universitätsklinik und Poliklinik für Innere Medizin III, Martin-Luther-Universität Halle-Wittenberg, 06097 Halle (Saale).
authors.forename: Elena
authors.initials: E
authors.lastname: Westphal
authors.forename: Mona
authors.initials: M
authors.lastname: Herzberg
authors.forename: Ingo
authors.initials: I
authors.lastname: Neumann
authors.forename: Li
authors.initials: L
authors.lastname: Beibei
authors.forename: Claudia
authors.initials: C
authors.lastname: Pilowski
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.forename: Harald
authors.initials: H
authors.lastname: Loppnow
mesh_terms: D020170:Caspase 1 / Q000096:biosynthesis* / Q000235:genetics; D061945:Caspase Inhibitors; D002452:Cell Count; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D011498:Protein Precursors / Q000096:biosynthesis*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D061945:Caspase Inhibitors; D007375:Interleukin-1; D020382:Interleukin-18; D009842:Oligopeptides; D011498:Protein Precursors; D012333:RNA, Messenger; C118632:tyrosyl-valyl-alanyl-aspartal; D020170:Caspase 1