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)

Transforming growth factor-beta 1 (TGF-beta 1) is a cytokine with complex immunomodulatory effects including the ability to inhibit the onset or severity of autoimmune disease. This study was designed to test the possibility that one mechanism by which TGF-beta 1 exerts its immunosuppressive effects is by inducing antigen (Ag)-specific unresponsiveness in CD4+ cells. TGF-beta 1 was shown here to inhibit the Ag-specific proliferation of naive CD4+ cells from T cell receptor (TCR) transgenic mice. More importantly, the naive CD4+ cells exposed to TGF-beta 1 and Ag, but not to TGF-beta 1 alone, in primary cultures were unable to proliferate or secrete IL-2 in response to a subsequent Ag challenge following removal of TGF-beta 1 from the cultures. Anti-CD28 mAb partially blocked the Ag-specific inactivation induced by TGF-beta 1 in naive CD4+ cells. The inhibitory effects of TGF-beta 1 on CD4+ cells are not mediated by alterations in APC costimulation since TGF-beta 1 did not inhibit the Ag-induced expression of MHC class II molecules, CD80 or CD86 on splenic APC. Taken together, the results suggest that the immunosuppressive activities of TGF-beta 1 encompass direct induction of Ag-specific unresponsiveness in naive CD4+ cells.
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PMID:Transforming growth factor-beta 1 induces antigen-specific unresponsiveness in naive T cells. 924 66

APC and transforming growth factor-beta type II receptor (TGF-beta RII) gene mutations, and microsatellite instability have been found in sporadic colorectal carcinomas. To clarify further the early alterations in colorectal carcinogenesis, we investigated these genetic changes in 23 protruding- and 24 superficial-type mucosal colorectal carcinomas. TGF-beta RII gene mutations and microsatellite instability were rarely found in these lesions. Nevertheless, APC was mutated in 16 of the 47 (34.0%) mucosal colorectal carcinomas and was significantly more frequently mutated in protruding- (I) and superficial elevated-type (IIa) (14/32, 43.8%) than in other superficial-type (IIa+IIc, IIb, IIc, and IIc+IIa) (2/ 15, 13.3%) mucosal colorectal carcinomas (P < 0.04). These results indicate that the APC gene may be involved from the beginning in the tumorigenesis of many early colorectal carcinomas, particularly of the protruding and superficial elevated types. However, there might be a distinct pathway for other superficial-type colorectal carcinomas, possibly not involving APC as an initial step of tumorigenesis.
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PMID:Analyses of the APC and TGF-beta type II receptor genes, and microsatellite instability in mucosal colorectal carcinomas. 933 Jun 2

Immune privilege within the eye is due in large part to Ag-specific, systemic down-regulation of Th1 immune responses, a phenomenon termed anterior chamber-associated immune deviation (ACAID). Since the cytokine milieu influences Th cell differentiation, we hypothesized that TGF-beta, an immunosuppressive cytokine secreted by ocular cells, determines the nature of the immune response to Ags introduced into the anterior chamber. Accordingly, an in vitro model of the eye was used to determine the cytokine profile of ocular APC. TGF-beta preferentially induced APC to secrete a Th2-type cytokine, IL-10, and concomitantly suppressed the production of the Th1-inducing cytokine, IL-12. APC incubated with TGF-beta and anti-IL-10 Ab lost their ability to induce ACAID. In the absence of TGF-beta, Ag-pulsed APC preferentially secreted IL-12 and elicited Ag-specific Th1 responses (i.e., delayed-type hypersensitivity (DTH)). However, APC pulsed with Ag and exogenous IL-10 behaved in a manner similar to ocular APC and induced Ag-specific suppression of DTH. The role of IL-10 in ACAID was confirmed in IL-10 knockout mice. Anterior chamber injection of OVA into IL-10 knockout mice elicited normal DTH responses rather than ACAID. Moreover, Ag-pulsed APC from IL-10 knockout mice were unable to induce ACAID following in vitro treatment with TGF-beta. Thus, TGF-beta predisposes ocular APC to secrete IL-10 during Ag processing. This, in turn, directs the immune response away from a Th1 pathway and toward a Th2-like response in which DTH is suppressed.
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PMID:A novel role for TGF-beta and IL-10 in the induction of immune privilege. 949 45

Cancer in adenomas are thought to be an excellent model of colorectal carcinogenesis based on the adenoma-carcinoma sequence. We searched for alterations in the APC mutation cluster region, the whole coding regions of TGF-beta type II receptor (RII) and beta-catenin exon 3 in 16 cases of cancer in adenomas of the colon. Overexpression of the p53 protein was also analyzed. Nine of the 16 cases showed APC mutations in both the adenoma and cancer regions. Loss of heterozygosity in APC was found in one cancer in adenoma that had no mutation. p53 overexpression was detected in one adenoma and 10 cancerous regions, most of which also exhibited APC alterations. Two cases showed a missense mutation at codon 191 or loss of heterozygosity in TGF-beta RII in both the adenoma and cancer. Our data support the hypothesis that alterations of APC and p53 are responsible for most of the adenoma-carcinoma pathway, rather than TGF-beta RII alterations.
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PMID:Genetic alterations are frequent in APC but rare in the TGF-beta type II receptor gene in cancer in adenomas of the colon. 956 1

Frequent frameshift mutations of simple nucleotide repeats in the protein-encoding regions, as well as replication errors (RERs) at microsatellite loci, have recently been demonstrated in gastrointestinal tumors. These genetic instabilities have been considered indicative of an increased risk of accumulating mutations in cancer-associated genes and of developing multiple cancers. We studied frameshift (or insertion/deletion) mutations of simple nucleotide repeats in five genes (TGFbeta type II receptor [TGFbetaRII], E2F4, MSH2, MSH3, and MSH6) in 23 tumors from 12 patients who had synchronous cancers of the esophagus and other organs. Genetic instability at four microsatellite loci, as well as mutations in the TP53, APC, and KRAS2 genes, were also studied. No frameshift mutations were observed in the TGFbetaRII, MSH3, and MSH6 genes. RER and a deletion mutation of BAT26 in MSH2 were present in one (1/23; 4%) gastric cancer. This tumor also carried a deletion mutation in the serine (AGC) repeat of the E2F4 gene. Mutation screening of the TP53, APC, and KRAS2 genes revealed that the synchronous cancers did not carry the same mutations. Our results suggested that genetic instability, such as insertion/deletion mutations in simple nucleotide repeats, is not significantly associated with the development of multiple primary cancers of the esophagus and other organs, and that these synchronous cancers developed independently according to their different environmental factors.
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PMID:Infrequent frameshift mutations of polynucleotide repeats in multiple primary cancers affecting the esophagus and other organs. 982 4

Protection against intracellular bacteria by T cells is regulated by Ag-presenting molecules, which comprise classical MHC class I molecules, MHC class II molecules, and nonclassical MHC class Ib molecules. The role of CD1 molecules, which are structurally similar to classical MHC class I gene products, but less polymorphic, is not understood so far. We show that CD1 surface expression increased on APC in Listeria-infected mice. The in vivo treatment with anti-CD1 mAb reduced TGF-beta 2 levels and concomitantly increased secretion of the proinflammatory cytokine TNF, the Th1 cell promoting cytokine IL-12, and the Th1 cell cytokine IFN-gamma at the onset of listerial infection. These findings point to a regulatory role of CD1-reactive cells in the immune response against listeriosis.
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PMID:Cutting edge: anti-CD1 monoclonal antibody treatment reverses the production patterns of TGF-beta 2 and Th1 cytokines and ameliorates listeriosis in mice. 1035 32

Receptors that display negative signalling functions on lymphocytes and other cells of the reticuloendothelial system now number about 30. These negative receptors are transmembrane glycoproteins activated by phosphorylation of a tyrosine residue in immunoreceptor tyrosine-based inhibitory motifs that bind various phosphatases to induce dominant negative signals. Since these receptors are armed by the action of activating receptors and inhibit signalling by activating receptors, we have termed them coinhibitory receptors and the negative outcome is coinhibition. Coinhibitory receptors and some inhibitory mediators include FcgammaRIIB, CTLA-4, CD5, CD22, p58/70/140 KIR, gp49B1/gp91, PIRB1-5, LAIR-1, NKB1, Ly49 A/C/E/F/G, NKG2-A/B APC-R, CD66, CD72, PD-1, SHPS-1, SIRP-alpha1, ILT1-5, MIR7, 10, hMIR(HM18), hMIR(HM9), LIR1-3,5,8, Fas (CD95), TGFbeta-R, TNF-R1, IFNgamma-R (alpha and beta chains), mast cell function Ag, H2-M, HLA-DM, CD1, CD1-d, CD46, c-cbl, Pyk2/FADK2, P130 Ca rel prot, PGDF-R, LIF, LIF-R, CIS, SOCS13 and 5, and others are being defined regularly. This long list suggests that coinhibitors are needed not only for self-nonself discrimination, but also for control of ongoing responses to foreign antigens so that infectious agents are ideally dealt with by an appropriate level of immune responses to nonself and an appropriate amount of immunopathology and sickness behaviour.
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PMID:Why so many coinhibitory receptors? 1040 45

Oral administration of Ag leads to systemic unresponsiveness (oral tolerance) to the fed Ag. Oral tolerance is mediated through active suppression by Th2 or TGF-beta-secreting cells or clonal anergy/deletion, depending on the Ag dose used, with low dose favoring active suppression and high dose favoring anergy/deletion. The nature of APC and inductive events leading to the generation of oral tolerance have not been well defined. To determine the role of costimulatory molecules in the induction of oral tolerance, we have tested the effect of anti-B7.1 or anti-B7.2 mAb on the induction of tolerance by both high and low dose Ag feeding regimens. Our results show that the B7.2 molecule is critical for the induction of low-dose oral tolerance. Injection of anti-B7.2 but not anti-B7.1 intact Ab or Fab fragments inhibited the oral tolerance induced by low-dose (0.5 mg) but not high-dose OVA (25 mg) feeding. In addition, anti-B7.2, but not anti-B7.1, inhibited secretion of TGF-beta, one of the primary cytokines that mediates low-dose oral tolerance. Finally, in the in vivo model of experimental allergic encephalomyelitis, anti-B7.2 mAb treatment abrogated protection offered against disease by low-dose myelin basic protein feeding, while anti-B7.1 had no effect. Anti B7.2 had no effect on disease suppression by high-dose oral Ag. These data demonstrate that B7.2 costimulatory molecules play an essential role in the induction of low-dose oral tolerance.
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PMID:B7.2 (CD86) but not B7.1 (CD80) costimulation is required for the induction of low dose oral tolerance. 1043 73

B cells convert what are normally conditions for Th1 differentiation into an environment suitable for Th2 development. This capacity is dependent on CD40 as B cells from CD40-/- mice do not elicit Th2 differentiation. To elucidate the basis of this effect, we surveyed cytokine RNA made by naive B cells after activation with anti-Ig and anti-CD40. Resting B cells make TGF-beta message only, however, 4 days after activation, RNA encoding IL-6, IL-10, and TNF-alpha was found. The expression of these messages was accelerated by 2 days in the presence of IL-12. The relevance of these observations to T cell differentiation was investigated: addition of OVA peptide to splenic cells from DO.11.10 transgenic mice causes most T cells to make IFN-gamma. Coactivation of B cells in these cultures reduces the number of IFN-gamma-producing T cells and increases the number synthesizing IL-4. Abs to IL-6 and IL-10 block the IL-4 enhancement. Dissection of the component APC demonstrated that interaction of B cells with IL-12-producing dendritic cells is crucial for B cell-mediated IL-4 enhancement: Thus, B cells preactivated in the presence of dendritic cells from IL-12-/- mice show little IL-4-inducing activity when used to activate T cells. This immune regulation is initiated by IL-12 and therefore represents a feedback loop to temper its own dominant effect (IFN-gamma induction).
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PMID:Dendritic cell-derived IL-12 promotes B cell induction of Th2 differentiation: a feedback regulation of Th1 development. 1051 Mar 67

Both genetic and epigenetic factors contribute to the development of colorectal cancer. Specific genetic changes in proto-oncogenes, tumor suppressor genes, and DNA mismatch repair genes have led to a genetic model of colorectal tumorigenesis. Recent data highlight the importance of the TGF-beta signaling pathway in regulating the progression of colorectal cancer. The loss of the tumor suppressor activity of this pathway as well as the potentially cooperative genetic aberrations involving APC, K-ras, and p53 are reviewed in the context of the multi-step adenoma-carcinoma sequence that characterizes the development of colorectal tumorigenesis. In addition, contributing epigenetic factors including age, diet, angiogenesis, and immune response are also discussed. Combining our knowledge of the genetic and epigenetic events implicated in this disease may allow a broader understanding of the pathogenesis of colorectal cancer and hence the design of better anti-tumor interventions.
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PMID:Genetic and epigenetic contributions to colorectal cancer. 1051 22


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