HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Seshadri, S. Articles by Wewers, M. D. Search for Related Content PubMed PubMed Citation Articles by Seshadri, S. Articles by Wewers, M. D.

Pyrin Levels in Human Monocytes and Monocyte-Derived Macrophages Regulate IL-1 Processing and Release¹

Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210

Macrophages and their precursors, monocytes, are key cells involved in the innate immune response. Although both monocytes and macrophages produce caspase-1, the key enzyme responsible for pro-IL-1 processing; macrophages are limited in their ability to activate the enzyme and release functional IL-1. In this context, because mutations in the pyrin gene (MEFV) cause the inflammatory disorder familial Mediterranean fever, pyrin is believed to regulate IL-1 processing. To determine whether variations in pyrin expression explain the difference between monocytes and macrophages in IL-1 processing and release, pyrin was studied in human monocytes and monocyte-derived macrophages. Although monocytes express pyrin mRNA and protein, which is readily inducible by endotoxin, monocyte-derived macrophages express significantly less pyrin mRNA and protein. Pyrin levels directly correlated with IL-1 processing in monocytes and macrophages; therefore, we asked whether pyrin might promote IL-1 processing and release. HEK293 cells were transfected with pyrin, caspase-1, apoptotic speck protein with a caspase recruitment domain, and IL-1. Pyrin induced IL-1 processing and release in a dose-dependent manner. Conversely, pyrin small interference RNA suppressed pro-IL-1 processing in both THP-1 cells and fresh human monocytes. In summary, both pyrin expression and IL-1 processing and release are diminished upon the maturation of monocytes to macrophages. When pyrin is ectopically expressed or silenced, IL-1 processing and release parallels the level of pyrin. In conclusion, in the context of endotoxin-induced activation of mononuclear phagocytes, pyrin augments IL-1 processing and release.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL40871 and HL76278.

² Address correspondence and reprint requests to Dr. Mark D. Wewers, Professor of Medicine, Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210. E-mail address: wewers.2{at}osu.edu

³ Abbreviations used in this paper: PYD, N-terminal pyrin domain; FMF, familial Mediterranean fever; CARD, caspase recruitment domain; ASC, apoptotic speck protein with a CARD; siRNA, small interference RNA; qPCR, quantitative PCR.

This article has been cited by other articles:

				M. A. Gavrilin, S. Mitra, S. Seshadri, J. Nateri, F. Berhe, M. W. Hall, and M. D. Wewers Pyrin Critical to Macrophage IL-1{beta} Response to Francisella Challenge J. Immunol., June 15, 2009; 182(12): 7982 - 7989. [Abstract] [Full Text] [PDF]

				M. G. Netea, C. A. Nold-Petry, M. F. Nold, L. A. B. Joosten, B. Opitz, J. H. M. van der Meer, F. L. van de Veerdonk, G. Ferwerda, B. Heinhuis, I. Devesa, et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1{beta} in monocytes and macrophages Blood, March 5, 2009; 113(10): 2324 - 2335. [Abstract] [Full Text] [PDF]

				J. J. Chae, G. Wood, K. Richard, H. Jaffe, N. T. Colburn, S. L. Masters, D. L. Gumucio, N. G. Shoham, and D. L. Kastner The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-{kappa}B through its N-terminal fragment Blood, September 1, 2008; 112(5): 1794 - 1803. [Abstract] [Full Text] [PDF]

				R. J. Fahy, M. C. Exline, M. A. Gavrilin, N. Y. Bhatt, B. Y. Besecker, A. Sarkar, J. L. Hollyfield, M. D. Duncan, H. N. Nagaraja, N. L. Knatz, et al. Inflammasome mRNA Expression in Human Monocytes during Early Septic Shock Am. J. Respir. Crit. Care Med., May 1, 2008; 177(9): 983 - 988. [Abstract] [Full Text] [PDF]

				C. Stehlik and A. Dorfleutner COPs and POPs: Modulators of Inflammasome Activity J. Immunol., December 15, 2007; 179(12): 7993 - 7998. [Abstract] [Full Text] [PDF]