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Infection and Immunity, April 2001, p. 2123-2129, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2123-2129.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Preexposure of Murine Macrophages to CpG Oligonucleotide Results in a Biphasic Tumor Necrosis Factor Alpha Response to Subsequent Lipopolysaccharide Challenge

Traves D. Crabtree,1 Long Jin,1 Daniel P. Raymond,1 Shawn J. Pelletier,1 C. Webster Houlgrave,1 Thomas G. Gleason,1 Timothy L. Pruett,1,2 and Robert G. Sawyer1,*

Surgical Infectious Disease Laboratory, Department of Surgery,1 and Department of Internal Medicine2, University of Virginia, Charlottesville, Virginia 22908

Received 17 August 2000/Returned for modification 11 October 2000/Accepted 8 January 2001

Bacterial DNA and synthetic oligonucleotides containing CpG sequences (CpG-DNA and CpG-ODN) provoke a proinflammatory cytokine response (tumor necrosis factor alpha [TNF-alpha ], interleukin-12 [IL-12], and IL-6) and increased mortality in lipopolysaccharide (LPS)-challenged mice via a TNF-alpha -mediated mechanism. It was hypothesized that preexposure of macrophages to CpG-ODN would result in an increased TNF-alpha response to subsequent LPS challenge in vitro. Using the murine macrophage cell line RAW 264.7, we demonstrated both a rapid proinflammatory cytokine response (TNF-alpha ) and a delayed inhibitory cytokine response (IL-10) with CpG-ODN. Preexposure of macrophages to CpG-ODN for brief periods (1 to 3 h) augmented TNF-alpha secretion and mRNA accumulation following subsequent LPS challenge (1 µg/ml). However, prolonged preexposure to CpG-ODN (6 to 9 h) resulted in suppression of the TNF-alpha protein and mRNA response to LPS. The addition of anti-IL-10 antibody to CpG-ODN during preexposure resulted in an increase in the LPS-induced TNF-alpha response over that induced by CpG-ODN preexposure alone. Thus, while brief preexposure of macrophages to CpG-ODN augments the proinflammatory cytokine response to subsequent LPS challenge, prolonged preexposure elicits IL-10 production, which inhibits the TNF-alpha response. Although the initial proinflammatory effects of CpG-DNA are well established, the immune response to CpG-DNA may also include autocrine or paracrine feedback mechanisms, leading to a complex interaction of proinflammatory and inhibitory cytokines.

* Corresponding author. Mailing address: Department of Surgery, UVA Health Systems, P.O. Box 800709, Charlottesville, VA 22908-0709. Phone: (804) 982-1632. Fax: (804) 924-5539. E-mail: rws2k{at}virginia.edu.

Infection and Immunity, April 2001, p. 2123-2129, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2123-2129.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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