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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2324-2335.
Prepublished online as a Blood First Edition Paper on December 22, 2008; DOI 10.1182/blood-2008-03-146720.
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Submitted March 25, 2008
Accepted September 16, 2008
Differential requirement for the activation of the inflammasome for processing and release of IL-1 in monocytes and macrophages
Mihai G. Netea*, Claudia A Nold-Petry, Marcel F. Nold, Leo A.B. Joosten, Bastian Opitz, Jonathan H.M. van der Meer, Frank L. van de Veerdonk, Gerben Ferwerda, Bas Heinhuis, Isabel Devesa, C. Joel Funk, Robert J. Mason, Bart Jan Kullberg, Anna Rubartelli, Jos W.M. Van der Meer, and Charles A. Dinarello
Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO, United States
Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charite-Universitatsmedizin, Berlin, Germany
Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Department of Medicine, National Jewish Medical and Research Center, Denver, CO, United States
Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, Netherlands
Department of Experimental Oncology E (Cell Biology), Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
* Corresponding author; email: m.netea{at}aig.umcn.nl.
The processing of pro-IL-1 depends on activation of caspase-1. Controversy has arisen whether TLR ligands alone can activate caspase-1 for release of IL-1. Here we demonstrate that human blood monocytes release processed IL-1 after a one-time stimulation with either TLR2 or TLR4 ligands, due to constitutively activated caspase-1 and release of endogenous ATP. The constitutive activation of caspase-1 depends on the inflammasome components ASC and NALP3, but in monocytes caspase-1 activation is uncoupled from PAMP recognition. In contrast, macrophages are unable to process and release IL-1 solely by TLR ligands, and require a second ATP stimulation. We conclude that IL-1 production is differentially regulated in monocytes and macrophages, and reflects their separate functions in host defense and inflammation.
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