The respiratory gene cox2, normally present in the mitochondrion, was previously shown to have been functionally transferred to the nucleus during flowering plant evolution, possibly during the diversification of legumes. To search for novel intermediate stages in the process of intracellular gene transfer and to assess the evolutionary timing and frequency of cox2 transfer, activation, and inactivation, we examined nuclear and mitochondrial (mt) cox2 presence and expression in over 25 legume genera and mt cox2 presence in 392 genera. Transfer and activation of cox2 appear to have occurred during recent legume evolution, more recently than previously inferred. Many intermediate stages of the gene transfer process are represented by cox2 genes in the studied legumes. Nine legumes contain intact copies of both nuclear and mt cox2, although transcripts could not be detected for some of these genes. Both cox2 genes are transcribed in seven legumes that are phylogenetically interspersed with species displaying only nuclear or mt cox2 expression. Inactivation of cox2 in each genome has taken place multiple times and in a variety of ways, including loss of detectable transcripts or transcript editing and partial to complete gene loss. Phylogenetic evidence shows about the same number (3-5) of separate inactivations of nuclear and mt cox2, suggesting that there is no selective advantage for a mt vs. nuclear location of cox2 in plants. The current distribution of cox2 presence and expression between the nucleus and mitochondrion in the studied legumes is probably the result of chance mutations silencing either cox2 gene. Most of these recent evolutionary transfers involve mt genes in plants (e.g., refs. 3-9); in contrast, the numerous sequenced mt genomes of animals all contain the same set of 13 (or occasionally 12) protein genes (10).Previously characterized cases of gene transfer have revealed several intermediate stages in the process of intracellular gene transfer. In most cases, physical transfer of plant mt genes has been inferred to occur by an RNA intermediate because the nuclear copy resembles an edited mt mRNA rather than an unedited mt gene (e.g., refs. 3-5). Acquisition of regulatory elements and a mt targeting sequence is critical for nuclear gene activation. This has been inferred to have occurred by recombination with a duplicated targeting sequence from a preexisting nuclear gene encoding a mt protein (6), by alternative splicing of a targeting sequence shared with a preexisting mitochondrialtargeted gene (8, 9), and by exon shuffling from a nuclear gene encoding a cytosolic protein and gain of mt targeting function (11). After nuclear gene activation, both the nuclear and mt copies should be expressed, at least transiently, but no such examples have been reported previously in plants. Inactivation (silencing) and loss have been reported only for the organellar copy but not the nuclear copy, suggesting that inactivation of the organellar gene is favored.The respiratory gene cox2, encoding subunit 2 of cy...
In this study four murine IL-12 naked DNA expression plasmids (pIL-12), containing both the p35 and p40 subunits, were shown to induce systemic biological effects in vivo after intradermal injection. Three of the four IL-12 expression vectors augmented NK activity and induced expression of the IFN-γ and IFN-γ-inducible Mig genes. Both IL-12 p70 heterodimer and IFN-γ proteins were documented in the serum within 24 h after intradermal injection of the pIL-12o− plasmid, which also induced the highest level of NK activity in the spleen and liver among the IL-12 constructs. Interestingly, both p40 mRNA expression at the injection site and serum protein levels followed a biphasic pattern of expression, with peaks on days 1 and 5. Subsequent studies revealed that the ability of intradermally injected pIL-12o− to augment NK lytic activity was prevented by administration of a neutralizing anti-IL-12 mAb. Finally, injection of the pIL-12o− into BALB/c IL-12 p40−/− mice also resulted in a biphasic pattern of IL-12 p70 appearance in the serum, and induced IFN-γ protein and activated NK lytic activity in liver and spleen. These results demonstrate that injection of delivered naked DNA encoding the IL-12 gene mediates the biphasic systemic production of IL-12-inducible genes and augments the cytotoxic function of NK cells in lymphoid and parenchymal organs as a direct result of transgene expression. The results also suggest that these naked DNA plasmids may be useful adjuvants for vaccines against infectious and neoplastic diseases.
NK cells have been shown to be important antitumor or antiviral effector cells in the liver. In the present study we have examined the factors that regulate the initial recruitment and subsequent fate of hepatic NK and T cells in mice treated with IL-12 or IL-2. Daily administration of IL-12 caused a rapid initial increase in NK cells followed by a subsequent decrease that coincided with an accumulation of T cells. The recruitment of hepatic NK cells by IL-12, but not the subsequent T cell infiltrate, was abrogated in IFN-γ−/− mice. In contrast, daily administration of IL-2 caused a sustained increase in liver-associated NK cells that was not diminished in IFN-γ−/− mice. The IL-12-induced recruitment in both hepatic NK and T cells was abrogated by in vivo treatment with anti-VCAM-1 mAbs, while treatment with anti-ICAM-1 Abs decreased only the recruitment of T cells in the IL-12-treated mice. The rapid loss of newly recruited hepatic NK cells in IL-12-treated mice did not occur in SCID mice or in B.MRL-Faslpr (Fas−) and B6Smn.C3H-Faslgld (FasL−) mutant mice, suggesting that T cells can actively eliminate hepatic NK cells through a Fas-dependent mechanism. These findings also imply that during the endogenous innate immune response to infectious agents or tumors or in the host response induced by cytokine therapies, the biologic effects of NK cells may be limited by T cell-mediated effects.
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