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Molecular and Cellular Biology, June 2006, p. 4214-4225, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01751-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Novel Lymphotoxin Alpha (LT{alpha}) Knockout Mice with Unperturbed Tumor Necrosis Factor Expression: Reassessing LT{alpha} Biological Functions{dagger}

Dmitry J. Liepinsh,1,2 Sergei I. Grivennikov,2,6 Kimberly D. Klarmann,1,3 Maria A. Lagarkova,6 Marina S. Drutskaya,3,6 Stephen J. Lockett,4 Lino Tessarollo,5 Matthew McAuliffe,7 Jonathan R. Keller,1,3 Dmitry V. Kuprash,2,6 and Sergei A. Nedospasov6*

Basic Research Program, SAIC-Frederick, Inc.,1 Basic Research Laboratory,2 Cancer and Developmental Biology Laboratory,3 Image Analysis Laboratory,4 Mouse Cancer Genetics Program, Center for Cancer Research, NCI—Frederick, Frederick, Maryland 21702,5 Laboratory of Molecular Immunology, Belozersky Institute of Physico-Chemical Biology, Moscow State University, and Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia,6 Center for Information Technology, DCB, ISL, BIRSS, National Institutes of Health, Bethesda, Maryland 208927

Received 6 September 2005/ Returned for modification 4 November 2005/ Accepted 3 January 2006

Lymphotoxin alpha (LT{alpha}) can exist in soluble form and exert tumor necrosis factor (TNF)-like activity through TNF receptors. Based on the phenotypes of knockout (KO) mice, the physiological functions of LT{alpha} and TNF are considered partly redundant, in particular, in supporting the microarchitecture of the spleen and in host defense. We exploited Cre-LoxP technology to generate a novel neomycin resistance gene (neo) cassette-free LT{alpha}-deficient mouse strain (neo-free LT{alpha} KO [LT{alpha}{Delta}/{Delta}]). Unlike the "conventional" LT{alpha}–/– mice, new LT{alpha}{Delta}/{Delta} animals were capable of producing normal levels of systemic TNF upon lipopolysaccharide (LPS) challenge and were susceptible to LPS/D-galactosamine (D-GalN) toxicity. Activated neutrophils, monocytes, and macrophages from LT{alpha}{Delta}/{Delta} mice expressed TNF normally at both the mRNA and protein levels as opposed to conventional LT{alpha} KO mice, which showed substantial decreases in TNF. Additionally, the spleens of the neo-free LT{alpha} KO mice displayed several features resembling those of LTß KO mice rather than conventional LT{alpha} KO animals. The phenotype of the new LT{alpha}{Delta}/{Delta} mice indicates that LT{alpha} plays a smaller role in lymphoid organ maintenance than previously thought and has no direct role in the regulation of TNF expression.

* Corresponding author. Mailing address: Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov St., 119991 Moscow, Russia. Phone: 7 (495) 135-9964. Fax: 7 (495) 135-1405. E-mail: snedos{at}online.ru.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2006, p. 4214-4225, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01751-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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