Open Access

ARTICLE

Neutrophils process interleukin-1β and interleukin-18 precursors in a caspase-1-like fashion – processing is inhibited by human vascular smooth muscle cells

Elena Westphal^1,*, Mona Herzberg^2,*, Ingo Neumann^1,**, Li Beibei¹, Claudia Pilowski¹, Chen Li¹, Karl Werdan¹, Harald Loppnow^1,2

1 Universitätsklinik und Poliklinik für Innere Medizin III, Martin-Luther-Universität Halle-Wittenberg, 06097 Halle (Saale)
2 Abteilung Immunologie und Zellbiologie, Forschungszentrum Borstel, 23845 Borstel, Germany

* Corresponding Author: H. Loppnow,

European Cytokine Network 2006, 17(1), 19-28.

Accepted 20 February 2006;

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-1β precursor molecule. Invading leukocytes, such as monocytes or polymorphonuclear granulocytes (PMN) may activate the IL-1β precursor during atherogenesis. Thus, we investigated the capacity of PMN to process IL-1β 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-1β. PMN also cleaved the caspase-1 substrate preIL-18. The preIL-1β 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-1b 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-1β or preIL-18 depending on the cell number, whereas EC or fibroblasts did not block processing. Our results indicate that PMN can activate preIL-1β in a caspase-1-like fashion. During inflammatory processes, PMN may activate preIL-1β released from SMC, thereby altering IL-1-mediated cardiovascular functions, including contractility, apoptosis, and cytokine production.

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