Expression of human group II PLA2 in transgenic mice results in epidermal hyperplasia in the absence of inflammatory infiltrate.

Group II PLA2 has been implicated in inflammatory processes in both man and other animals and has been shown to be involved in inflammatory conditions, such as arthritis and sepsis. Transgenic mice expressing the human group II PLA2 gene have been generated using a 6.2-kb genomic fragment. These mice express the group II PLA2 gene abundantly in liver, lung, kidney, and skin, and have serum PLA2 activity levels approximately eightfold higher than nontransgenic littermates. The group II PLA2 transgenic mice reported here exhibit epidermal and adnexal hyperplasia, hyperkeratosis, and almost total alopecia. The chronic epidermal hyperplasia and hyperkeratosis seen in these mice is similar to that seen in a variety of dermatopathies, including psoriasis. However, unlike what is seen with these dermatopathies, no significant inflammatory-cell influx was observed in the skin of these animals, or in any other tissue examined. These mice provide an important tool for examining group II PLA2 expression, and for determining the role of group II PLA2 in normal and disease physiology. They serve as an in vivo model for identifying inhibitors of group II PLA2 activity and gene expression.

Transgenic mice expressing both human apolipoprotein B and human CETP have a lipoprotein cholesterol distribution similar to that of normolipidemic humans.

Transgenic mice expressing both human apolipoprotein (apo) B and human cholesteryl ester transfer protein (CETP) have been developed. When fed a normal mouse chow diet, the apoB/CETP double transgenic animals had threefold higher serum CETP activity than humans and had human apoB levels that were similar to those of normolipidemic humans. When compared with nontransgenic mice, the total serum cholesterol levels in the female apoB/CETP transgenic animals were increased significantly. Serum HDL cholesterol levels were decreased significantly in both male and female apoB/CETP transgenic animals. The percentages of the total cholesterol within the HDL, LDL, and VLDL fractions of the apoB/CETP animals were approximately 30%, 65%, and 5%, respectively, similar to the distribution of cholesterol in the plasma of normolipidemic humans. Thus, by expressing both human apoB and human CETP, the lipoprotein cholesterol distribution in the serum of a chow-fed mouse was transformed into one that resembles a human profile.

Mutational analysis of the N-linked glycosylation sites of the SU envelope protein of Moloney murine leukemia virus.

The role of the N-linked glycosylation sites in the major envelope glycoprotein, SU (gp70), of Moloney murine leukemia virus has been examined. By using site-specific oligonucleotide-directed mutagenesis, each of the seven glycan addition sites has been individually eliminated. Mutations resulting in the loss of a single glycosylation site produced, intracellularly, stable precursor SU-TM proteins which were 4 to 5 kDa smaller than the wild-type virus SU-TM protein. Mutant delta 1,4,7, a trimutant lacking three N-linked glycan addition sites, resulted in a viable, infectious virus with a stable SU-TM protein approximately 12 to 15 kDa smaller than the wild-type SU-TM protein. Five of the seven single-site mutations resulted in viable virus as judged by the release of reverse transcriptase in transient-expression assays and XC syncytium assays. Mutations at two of the sites resulted in a detectable phenotype. Virus mutated at position 2 was temperature sensitive in Rat2 cells; viable virus was produced at 32 degrees C but not at 37 degrees C. Virus mutated at position 3 was noninfectious and yielded virions lacking detectable mature SU protein. The mutation results in the block of transport of the protein to the cell surface and assembly into virion particles.