Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As reported previously, gamma interferon (IFN-gamma) production was selectively decreased in thermally injured mice (TI-Mice) and spleen cell cultures from the mice following stimulation with various IFN inducers. The decrease in IFN production was associated with splenic suppressor macrophages. The present study demonstrated that TI-Mice treated with Ge-132 (TGe-Mice) produced IFN following stimulation with IFN-gamma inducers. The level of IFN activity detected in the sera of TGe-Mice approximated that of controls. Similar results were obtained when spleen cells prepared from TGe-Mice were stimulated with IFN-gamma inducers in vitro. While transfer of spleen cells from TI-Mice resulted in the suppression of IFN production in normal mice (N-Mice) stimulated with IFN-gamma inducers, the transfer of spleen cells derived from TGe-Mice did not induce suppression of IFN production in N-Mice. Mononuclear cells (MNC) prepared from N-Mice produced IFN following concanavalin A (Con A) stimulation when they were co-cultured with macrophage-enriched populations (PAC) obtained from the spleens of TGe-Mice. In contrast, MNC stimulated with Con A did not produce IFN activity when they were co-cultured with PAC of TI-Mice. These results suggest that the generation of suppressor macrophages in TI-Mice may be altered by the administration of Ge-132.
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PMID:Prevention of suppressed interferon gamma production in thermally injured mice by administration of a novel organogermanium compound, Ge-132. 643 Oct 19

The MRL/lpr mouse is an inbred strain widely accepted as a model for autoimmune disease both in murine and human systems. Developed from a series of crosses involving four strains of mice, the MRL/lpr (H-2k) genome is a composite estimated to contain approximately 75% of its parental LG/J (H-2d) genome. To explore the cellular mechanism underlying lymphoproliferation in the MRL/lpr mouse, we have isolated a series of clones from the lymph nodes of MRL/lpr mice with autoimmune disease. Extensive immunofluorescent analyses of these clones, designated the PAC series, reveal expression of IAk and IEk (beta-chain) cell surface antigens, as well as inappropriate expression of IAd, IEd (beta-chain), and H-2d. PAC cells also express MAC-1, MAC-2, RA3-2C2, and RA3-6B2 and contain esterase-positive cytoplasmic granules. The capacity of PAC cells to present antigen was investigated by co-culturing PAC with IA-restricted, antigen-specific T cell hybridomas +/- antigen. These assays demonstrated the PAC inability to present antigen to IAk-restricted T cell hybridomas, as well as their capacity to present antigen to IAd-restricted T cell hybridomas. In addition, activation of MRL/lpr peritoneal macrophages using gamma-interferon resulted in increased fluorescent staining for IAd and IEd concomitant with decreased fluorescent staining for IAk. Based on these findings, we propose a model of lymphoproliferation in which Ly-1+, H-2K+ T cells proliferate to inappropriate d haplotype antigens expressed by a small subset of monocytes in the MRL/lpr lymph node. The major genomic contribution of the LG/J (H-2d) mouse may be in part responsible for inappropriate antigen expression either by age-dependent expansion of d haplotype cells or by age-regulated expression of Iad and H-2d genes.
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PMID:The isolation and functional characterization of autoimmune clones expressing inappropriate Ia. 661 Jul 12

IL-10 gene transcription and IL-10 protein production was assessed in both type 1 (Th1) and type 2 (Th2) CD4+ human T cell clones by polymerase chain reaction and ELISA, respectively. Although Th2 clones apparently showed higher IL-10 mRNA levels, IL-10 mRNA expression was consistently found in Th1 clones, as well. Likewise, measurable IL-10 levels were found in the supernatants of both Th1 and Th2 clones. The effect of human IL-10 (h-IL-10) and viral IL-10 (v-IL-10) on the proliferative response and cytokine production by Th1 and Th2 human clones was also investigated. Addition in culture of h-IL-10 and v-IL-10 significantly reduced the proliferation of both Th1 and Th2 clones in response to the specific Ag and to PHA, but it had no inhibitory effect on the proliferative response of Th1 and Th2 clones to IL-2. h-IL-10 and v-IL-10 also inhibited the Ag-induced production of gamma-interferon (IFN-gamma) by Th1 clones and the production of IL-4 and IL-5 by Th2 clones, whereas they had no effect on the cytokine synthesis by the same clones stimulated with PMA plus anti-CD3 antibody. Preincubation of APC, but not of clonal T blasts, with h-IL-10 resulted in the inhibition of Ag-induced proliferation of both Th1 and Th2 clones, supporting the view that h-IL-10 primarily affects APC. These data demonstrate that, unlike the murine system where IL-10 is a product of Th2 (but not Th1) cells and seems to mainly down-regulate the Th1 response, in the human system, IL-10 is produced by, and down-regulates the function of, both Th1 and Th2 cells.
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PMID:Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. 841 68

Lung cancers exhibit multiple genetic lesions including mutations activating the dominant cellular proto-oncogenes as well as those inactivating the recessive or "tumor suppressor" genes. Candidate tumor suppressor genes include those on chromosomes 1p, 1q, 3p14, 3p21.3, 3p25 (VHL gene), 5q21 (APC/MCC gene cluster), 9p21-22 (interferon gene cluster), 11p, 13q (rb gene), 16p24, and 17p (p53 gene). Mutations in p53 inactivate its transcriptional activity, while replacement of a wild-type p53 in lung cancer cells inhibits growth and tumorigenicity suggesting that p53 acts as a master growth regulatory switch. Lung cancer cells exhibit several positive autocrine growth factor loops and express nicotine receptors which could function as tumor promoting systems. In addition, they express a negative autocrine loop involving opioids and their receptors which is reversed by nicotine acting through nicotinic acetylcholine receptors. The presence of nicotine receptors suggests nicotine or its metabolites may play a direct role in lung cancer pathogenesis.
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PMID:The molecular biology of lung cancer pathogenesis. 846 39

Colon carcinomas appear to arise from the cumulative effect of mutations to several genes (APC, DCC, p53, ras, hMLH1, and hMSH2). By using novel colonic epithelial cell lines derived from the Immorto mouse, named the YAMC (young adult mouse colon) cell line, and an Immorto-Min mouse hybrid, named the IMCE (Immorto-Min colonic epithelial) cell line, carrying the Apc min mutation, we investigated the effect of an activated v-Ha-ras gene on tumor progression. The YAMC and IMCE cell lines are normal colonic epithelial cell lines which are conditionally immortalized by virtue of expression of a temperature-sensitive simian virus 40 (SV40) large T antigen. Under conditions which permit expression of a functional SV40 large T antigen (33 degrees C plus gamma interferon), neither the YAMC nor the IMCE cell line grows in soft agar or is tumorigenic in nude mice. In vitro, when the SV40 large T antigen is inactivated (39 degrees C without gamma interferon), the cells stop proliferating and die. By infecting the YAMC and IMCE cell lines with a replication-defective psi2-v-Ha-ras virus, we derived cell lines which overexpress the v-Ha-ras gene (YAMC-Ras and IMCE-Ras). In contrast to the parental cell lines, under conditions in which the SV40 large T antigen is inactive, both the YAMC-Ras and IMCE-Ras cell lines continue to proliferate. Initally YAMC-Ras cells do not form tumors; however, tumors are visible after 90 days of incubation. IMCE-Ras cells form colonies in soft agar under both permissive and nonpermissive culture conditions. Furthermore, IMCE-Ras cells form tumors in nude mice within 3 weeks. The phenotype of the IMCE-Ras cell line thus clearly demonstrates that a defective Apc allele and an activated ras gene are sufficient to transform normal colonic epithelial cells and render them tumorigenic.
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PMID:Synergy between Apc min and an activated ras mutation is sufficient to induce colon carcinomas. 862 90

The present study examined self-tolerance for T cell receptor (TCR) alpha beta intestinal intraepithelial lymphocytes (iIELs) using the 2C transgenic (Tg) mouse model specific for a peptide antigen (Ag) presented by the class I major histocompatibility complex H-2Ld. Although Tg+ T cells were largely deleted from the periphery of Ag+ mice, equivalent numbers of Tg iIELs were present in Ag+ compared to Ag- mice. Tg iIELs in Ag- mice contained CD8 alpha beta, CD8 alpha alpha, and CD4-CD8- subsets, whereas only CD8 alpha alpha and CD4-CD8- Tg iIEL subsets were detected in Ag+ mice. Analysis of surface markers revealed that Tg iIELs in Ag+ mice expressed decreased levels of Thy-1 and increased CD45R/B220 as compared to Ag- Tg iIELs. In response to activation with exogenous peptide or immobilized anti-TCR mAB, iIELs from Ag- mice proliferated at high levels and produced interleukin (IL)-2 and interferon (IFN)-gamma, while Tg+ iIELs from Ag+ mice proliferated at low levels and failed to produce detectable IL-2 or IFN-gamma. Activation of sorted iIEL subsets from Ag- mice revealed that CD8 alpha alpha and CD4-CD8- subsets produced low levels of IL-2 and IFN-gamma in response to activation with antigen-presenting cells and added peptide or immobilized anti-TCR mAb, while CD8 alpha beta + iIELs responded to endogenous levels of peptide. In response to APC and exogenous peptide, sorted iIEL subsets from Ag+ mice produced IL-2 and IFN-gamma, and proliferated at greatly reduced levels compared to corresponding subsets from Ag- mice. Analysis of cytokine mRNA levels revealed that activation in vitro induced IL-2 mRNA only in Ag-, but not Ag+ iIELs, whereas a high level of IL-4 mRNA induction was detected in Tg+ iIELs from Ag+ mice, and to a lesser degree, from Ag- mice. These data suggest that tolerance for Tg+ iIELs resulted in the deletion of CD8 alpha beta + subsets and the persistence of Tg+ iIEL subsets with decreased sensitivity to endogenous levels of self-peptide. A comparison of the cytokine profiles expressed by Tg+ iIEL subsets in Ag- and Ag+ mice suggested that tolerance induction had involved the functional deviation of cells from TC1 (T helper-1-like) to a less inflammatory TC2 (T helper-2-like) phenotype capable of mediating humoral immune responses in the mucosa.
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PMID:Immune deviation of 2C transgenic intraepithelial lymphocytes in antigen-bearing hosts. 876 Aug 3

Lipopolysaccharide (LPS) from gram-negative bacteria causes polyclonal activation of B cells and stimulation of macrophages and other APC. We show here that, under in vivo conditions, LPS also induces strong stimulation of T cells. As manifested by CD69 upregulation, LPS injection stimulates both CD4 and CD8(+) T cells, and, at high doses, stimulates naive (CD44(lo)) cells as well as memory (CD44(hi)) cells. However, in terms of cell division, the response of T cells after LPS injection is limited to the CD44(hi) subset of CD8(+) cells. In contrast with B cells, proliferative responses of CD44(hi) CD8(+) cells require only very low doses of LPS (10 ng). Based on studies with LPS-nonresponder and gene-knockout mice, LPS-induced proliferation of CD44(hi) CD8(+) cells appears to operate via an indirect pathway involving LPS stimulation of APC and release of type I (alpha, beta) interferon (IFN-I). Similar selective stimulation of CD44(hi) CD8(+) cells occurs in viral infections and after injection of IFN-I, implying a common mechanism. Hence, intermittent exposure to pathogens (gram-negative bacteria and viruses) could contribute to the high background proliferation of memory-phenotype CD8(+) cells found in normal animals.
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PMID:T cell stimulation in vivo by lipopolysaccharide (LPS). 918 80

The 2',5'-oligoadenylate synthetases (OAS) represent a family of interferon-induced proteins implicated in the mechanism of the antiviral action of interferon. When activated by double-stranded RNA, these proteins polymerize ATP into 2'-5'-linked oligomers with the general formula pppA(2'p5'A)n, n >/= 1. Three forms of human OAS corresponding to proteins of 40/46, 69/71, and 100 kDa have been described. Based on the deduced amino acid sequences of the corresponding cDNAs, these OAS share a homologous region of about 350 amino acid residues that could represent the functional domain of OAS; the 40/46 proteins contain one single domain, whereas the 69/71- and the 100-kDa proteins contain two and three adjacent domains, respectively. Here we show that the cDNAs for OAS-40/46, OAS-69/71, and OAS-100 hybridize to distinct interferon-induced mRNAs of 2 kb; 2.8, 3.3, 3.9, and 4.5 kb; and 7 kb, respectively. By in situ hybridization, we assign the human OAS-40/46, OAS-69/71, and OAS-100 genes (referred to as OAS1, OAS2, and OAS3, respectively) to a unique cytogenetic location on chromosomal region 12q24.2. We constructed a YAC, PAC, and cosmid contig carrying the three OAS genes and provide evidence that the three genes are clustered within a single PAC clone of 130 kb. The three OAS genes are flanked by markers WI-10614 (cen) and D12S2293 (tel) and are contained within three sets of overlapping cosmid clones. They share the same orientation of transcription and are arranged in the order cen- 5'-OAS1-OAS3-OAS2-3'-tel. We suggest that clustering of these genes reflects their evolutionary relationship possibly through the duplication of the conserved functional domain. This ready-to-sequence PAC and cosmid contig provides a valuable tool for identifying regulatory elements involved in the transcription of the OAS genes when induced by interferon and for elucidating the exon-intron organization of these genes.
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PMID:The human 2',5'-oligoadenylate synthetase locus is composed of three distinct genes clustered on chromosome 12q24.2 encoding the 100-, 69-, and 40-kDa forms. 979 Jul 45

Mice immunized with peritoneal exudate cells (PEC; used as antigen-presenting cells [APC]) that are pulsed ex vivo with cryptococcal capsular polysaccharide, a glucuronoxylomannan (GXM), exhibit increased survival times and delayed-type hypersensitivity reactions when they are infected with Cryptococcus neoformans. These responses are GXM specific. The present study revealed that GXM-APC immunization enhanced development of anticryptococcal type-1 cytokine responses (interleukin-2 [IL-2] and gamma interferon) in mice infected with C. neoformans. The enhancement was not GXM specific, because immunization with GXM-APC and immunization with APC alone had similar effects. GXM-APC (or APC) immunization caused small increases in the expression of type-2 cytokines (IL-4 and IL-5), but the increases were not always statistically significant. IL-10 levels were not regulated by immunization with GXM-APC or APC. GXM-APC prepared with PEC harvested from mice injected with complete Freund's adjuvant (CFA) enhanced type-1 cytokine responses, while GXM-APC prepared with PEC induced with incomplete Freund's adjuvant were ineffective. The CFA-induced PEC had an activated phenotype characterized by increased numbers of F4/80(+) cells that expressed CD40, B7-1, and B7-2 on their membranes. The immunomodulatory activity of the CFA-induced APC population was not attributed to their production of IL-12 because GXM-APC prepared with peritoneal cells harvested from IL-12 knockout mice or their wild-type counterparts were equally effective in augmenting the type-1 response. Blocking of IL-12 in the recipients of GXM-APC early after APC infusion revealed that early induction of IL-12 secretion was not responsible for the immunomodulatory response elicited by GXM-APC. These data, considered together with previously reported data, reveal that the protective activity of GXM-APC immunization involves both antigen-specific and nonspecific activities of GXM-APC.
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PMID:Regulation of cytokine expression in mice immunized with cryptococcal polysaccharide, a glucuronoxylomannan (GXM), associated with peritoneal antigen-presenting cells (APC): requirements for GXM, APC activation, and interleukin-12. 1094 38

The protein kinase, interferon-inducible double-stranded (ds)RNA-dependent activator (PRKRA) is a dsRNA-binding protein which activates a protein kinase participating in the antiviral activity of interferon. Our previous studies indicated that the nucleotide sequence encoding PRKRA, which appeared to be an intronless gene, was present in PAC HS265J14 containing the human leukocyte antigen (HLA) DR subregion. In this study, we further investigated and characterized the PRKRA gene on the human genome by means of Southern blotting and polymerase chain reaction with homozygous typing cell lines for HLA genes. Results indicated that the presence of PRKRA in the DR subregion was dependent on the DR53 group. Consistently, fluorescence in situ hybridization profiles with PRKRA as a probe showed that the hybridization signal on Chromosome (Chr) 6p21.3 was seen only in the samples carrying the DR haplotypes that belonged to the DR53 group. Interestingly, another hybridization signal, which was mapped on Chr 2q31.2-q32.1, was always detected in the samples examined, i.e., even in the samples negative for the DR53 group. The outcome of a sequence-database homology search further indicated that the PRKRA gene with introns appeared to be present in a recently opened draft-sequence, RP11-65L3 (GenBank accession number AC009948), which is located between D2S335 and D2S2257. Together, the data presented here indicate that the PRKRA gene in the DR subregion is a processed pseudogene (PRKRApsi), which could have been generated only on the DR53 common ancestor's genome, and that the master copy of PRKRApsi is most probably present on Chr 2q31.2-q32.1.
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PMID:Haplotype-specific sequence encoding the protein kinase, interferon-inducible double-stranded RNA-dependent activator in the human leukocyte antigen class II region. 1122 Jun 20


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