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At least 145 records · Page 8Linked to original sources
PubMed1988

Up-regulation of c-fos expression is a component of the mIg signal transduction mechanism but is not indicative of competence for proliferation.

Control of entry into and progression through the early phases of cell cycle in B lymphocytes is poorly understood at the molecular level. Products of the c-fos proto-oncogene have been implicated in regulation of G0 to G1 cell cycle phase transition and cell proliferation in other systems. In view of these observations, the relationship between signals generated through receptor Ig which alter the B cells position in cell cycle and relative level of c-fos expression was investigated. Not unexpectantly, anti-Ig under conditions which promote G0-G1 and G1-S phase transition was observed to selectively up-regulate expression of c-fos. More interestingly, however, anti-Ig-induced cross-linking of surface Ig on the WEHI-231 B lymphoma also caused rapid and transient up-regulation of c-fos mRNA levels although it was associated with inhibition of proliferation of these cells. These results are important because they show that 1) c-fos expression is inducible in both normal and transformed B lymphocytes as a consequence of signals generated through receptor Ig, and 2) up-regulation of c-fos expression is not positively linked to B cell proliferation but rather appears to be a component of the surface Ig signal transduction mechanism. Finally, studies utilizing phorbol diesters suggest that pathways leading through protein kinase C are involved in both the growth inhibition and c-fos expression WEHI-231 following membrane-associated Ig cross-linking.

Animals↗
PubMed2005

Mapping of the critical region of mitogene-inducible gene-6 for NF-kappaB activation.

Mitogene-inducible gene-6 (Mig-6) is involved in the intracellular signaling pathway as an adaptor molecule. Mig-6 expression is rapidly induced upon various kinds of mitogenic and stressful stimulations. We previously demonstrated that Mig-6 expression is induced by activated Ki-ras in human colon cancer cells and the limited proteolytic processed NH(2)-terminal region containing the Cdc42/Rac interaction and binding (CRIB) domain of Mig-6 is bound to IkappaBalpha, resulting in NF-kappaB activation. In this study, we tried to determine the critical region of Mig-6 for regulating NF-kappaB activation by using various kinds of deletion-constructs of Mig-6. The CRIB domain-deleted Mig-6 fragment (residues 68 to 462) did not show significant NF-kappaB activation. Furthermore, NH(2)-terminal 148, 158 and 180 amino acid regions of Mig-6 did not show NF-kappaB activation. On the other hand, the NH(2)-terminal 264 amino acid region of Mig-6 did show NF-kappaB activation to a similar extent of the full length of Mig-6. Interestingly, the full length and NH(2)-terminal 264 amino acid region of Mig-6 produced two kinds of cleaved NH(2)-terminal fragments, N1 and N2 with an approximate molecular size of 5 and 7 kDa, respectively. The NH(2)-terminal 148 and 158 amino acid regions of Mig-6 did not produce N1 or N2 fragments, while the NH(2)-terminal 180 amino acid region of Mig-6 only produced the N1 fragment. Furthermore, the N2 fragment was bound with IkappaBalpha, but the N1 fragment was not. These results together suggested that the NH(2)-terminal 264 amino acid region is critical for NF-kappaB activation and proper limited proteolytic processing of Mig-6.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Infiltration of Th1 and Th2 lymphocytes around Hodgkin and Reed-Sternberg (H&RS) cells in Hodgkin disease: Relation with expression of CXC and CC chemokines on H&RS cells.

Hodgkin disease (HD) is characterized by the presence of Hodgkin and Reed-Sternberg cells (H&RS) and a prominent lymphocytic infiltration. Various CXC and CC chemokines [e.g., interferon-gamma-inducible protein-10 (IP10), monokine induced by interferon-gamma (MIG) and TARC] are expressed on H&RS cells. Our study was designed to investigate the expression of MIG, IP10 and TARC on H&RS cells and their relations on lymphocyte infiltration. Immunohistochemical staining was performed using antibodies for CXCR3 (a specific receptor for IP10 and MIG), which is characteristic of Th1 helper phenotype and CCR3, CCR4 and ST2, which are features of Th2 cells. We studied 15 cases of HD [lymphocyte predominance (LP) type, 2; mixed cellularity (MC) type, 6; and nodular sclerosis (NS) type, 7]. All 6 MC cases contained TARC-, IP10- and MIG-expressing H&RS cells, however only 2 of 5 NS cases contained TARC-expressing H&RS cells, 3 of 7 NS contained MIG-expressing H&RS cells and only 1 of 7 NS contained IP10-expressing H&RS cells. Neither of the 2 LP cases contained HR&S cells that expressed these chemokines. The chemokines were more frequently expressed by MC than by NS and LP types. IP10-, MIG- and TARC-positive HD cases contained higher numbers of Th2 lymphocytes (ST2- CCR3- or CCR4-positive lymphocytes), compared to IP10-, MIG- and TARC-negative HD cases (p < 0.05 or <0.5). The number of CXCR3 (MIG and IP10 receptor)-positive lymphocytes (Th1 lymphocytes) was not different between MIG- and IP10-positive and -negative HD. Lymphocytes surrounding MIG- and IP10-positive H&RS cells were more frequently CXCR3-positive, however, compared to MIG- and IP10-negative cases. The CCR4 (TARC receptor)-positive lymphocytes, surrounding H&RS cells, were minority and the surrounding lymphocytes were not different between TARC-positive and negative cases. Our results indicate that MIG, IP10 and TARC chemokines influenced the response of Th2 cells in HD. It is possible, however, that IP10 and MIG may locally influence Th1 cells via cell migration.

CD4 Antigens↗
PubMed2005

Monokine induced by interferon-gamma acts as a neurotrophic factor on PC12 cells and rat primary sympathetic neurons.

We found that a monokine induced by interferon-gamma (Mig, CXCL9), which belongs to the CXC chemokine subfamily, acts as a neurotrophic factor on PC12 cells and rat primary sympathetic neurons. PC12 cells were shown to express a single class of high affinity binding sites for Mig (670 receptors/cell, Kd = 2.9 nm). Mig induced neurite outgrowth in PC12 cells in a dose-dependent manner. Comparison of extracellular signal-regulated kinase signaling pathways between Mig and nerve growth factor (NGF) revealed that these pathways are crucial for Mig action as well as NGF. K252a, an inhibitor of tyrosine autophosphorylation of tyrosine kinase receptors (Trks) did not inhibit the action of Mig, suggesting that Mig action occurs via a different receptor from that of NGF. Furthermore, Mig as well as NGF promoted PC12 survival under serum-free conditions and activated Akt/protein kinase B downstream from phosphatidylinositol 3-kinase (PI3K). Because the PI3K inhibitor LY294002 prevented the Mig- and NGF-induced survival effect, this effect is probably mediated by the PI3K signaling pathway. Mig also promoted survival of rat primary sympathetic neurons that die when deprived of NGF. These results suggest that chemokines, including Mig (CXCL9) have neurotrophic effects on the nervous system.

Animals↗
PubMed1995

Intracellular targeting of antigens internalized by membrane immunoglobulin in B lymphocytes.

An important function of membrane immunoglobulin (mIg), the B cell antigen receptor, is to endocytose limiting quantities of antigen for efficient presentation to class II-restricted T cells. We have used a panel of mIg mutants to analyze the mechanism of mIg-mediated antigen presentation, and specifically to explore the ability of mIg to target internalized antigen to intracellular processing compartments. Transfected mIgs carrying substitutions for the transmembrane Tyr587 residue fail to efficiently present specifically bound antigen. However, these mutants internalize antigen normally, and their defect cannot be attributed to a lack of mIg-associated Ig alpha/Ig beta molecules. A novel functional assay for detecting antigenic peptides in subcellular fractions shows that wild-type mIg transfectants generate class II-peptide complexes intracellularly, whereas only free antigenic peptides are detectable in the mutant mIg transfectants. Furthermore, an antigen competition assay reveals that antigen internalized by the mutant mIgs fails to enter the intracellular processing compartment accessed by wild-type mIg. Therefore, mIg specifically targets bound and endocytosed antigen to the intracellular compartment where processed peptides associate with class II molecules, and the transmembrane Tyr587 residue plays an obligatory role in this process. Targeting of internalized antigen may be mediated by receptor-associated chaperones, and may be a general mechanism for optimizing the presentation of specifically bound and endocytosed antigens in b lymphocytes and other antigen-presenting cells.

Amino Acid Sequence↗
PubMed1999

Mutations affecting symmetrical migration of distal tip cells in Caenorhabditis elegans.

The rotational symmetry of the Caenorhabditis elegans gonad arms is generated by the symmetrical migration of two distal tip cells (DTCs), located on the anterior and posterior ends of the gonad primordium. Mutations that cause asymmetrical migration of the two DTCs were isolated. All seven mutations were recessive and assigned to six different complementation groups. vab-3(k121) and vab-3(k143) affected anterior DTC migration more frequently than posterior, although null mutants showed no bias. The other five mutations, mig-14(k124), mig-17(k113), mig-18(k140), mig-19(k142), and mig-20(k148), affected posterior DTC migration more frequently than anterior. These observations imply that the migration of each DTC is regulated differently. mig-14 and mig-19 also affected the migration of other cells in the posterior body region. Four distinct types of DTC migration abnormalities were defined on the basis of the mutant phenotypes. vab-3; mig-14 double mutants exhibited the types of DTC migration defects seen for vab-3 single mutants. Combination of mig-17 and mig-18 or mig-19, which are characterized by the same types of posterior DTC migration defects, exhibited strong enhancement of anterior DTC migration defects, suggesting that they affect the same or parallel pathways regulating anterior DTC migration.

Animals↗
PubMed1998

Prevalence of monoclonal immunoglobulins after liver transplantation: relationship with posttransplant lymphoproliferative disorders.

BACKGROUND: A high incidence of serum monoclonal immunoglobulins (mIgs) has been described after solid organ transplantation. For transplant recipients, the prevalence of posttransplant lymphoproliferative disorders (PTLDs) has been reported to be between 2% and 6%. The relationship between the finding of serum mIg in transplant recipients and the subsequent development of PTLDs is not clearly documented. METHODS: We retrospectively analyzed all cases of mIg and PTLD that occurred in 86 liver transplant recipients who survived more than 3 months. Patients were characterized by protein electrophoresis, immunofixation electrophoresis, pre- and post-liver transplantation Epstein-Barr virus (EBV) serology, EBV presence in lymphoproliferative tissues by in situ hybridization, type of infection episodes, rejection episodes, and immunosuppressive treatment. RESULTS: Thirty-eight patients (44%) had abnormal immunofixation electrophoresis with an electrophoretic Ig peak. Twelve patients had a polyclonal Ig peak, and 26 patients had mIgs (30%). These 26 patients were divided into two groups: 13 patients had a transient mIg peak with a mean delay for normalization of electrophoresis of 2 months, and 13 patients had a permanent mIg peak. No correlation could be demonstrated between the appearance of abnormal banding and indications for transplantation, age of patients, and acute rejection rate. There was a strong correlation between occurrence of viral infections and presence of permanent mIg. Three patients with permanent mIg (23%) developed PTLD and died. CONCLUSIONS: We concluded that the prevalence of mIg after liver transplantation was 30%. Viral infections increase the risk of developing mIg. Persistence of mIg beyond 7 months may be regarded as prelymphomas necessitating a careful follow-up in these patients.

Adolescent↗
PubMed2001

Monokine induced by IFN-gamma is a dominant factor directing T cells into murine cardiac allografts during acute rejection.

The use of chemokine antagonism as a strategy to inhibit leukocyte trafficking into inflammatory sites requires identification of the dominant chemokines mediating recruitment. The chemokine(s) directing T cells into cardiac allografts during acute rejection remain(s) unidentified. The role of the CXC chemokines IFN-gamma inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig) in acute rejection of A/J (H-2(a)) cardiac grafts by C57BL/6 (H-2(b)) recipients was tested. Intra-allograft expression of Mig was observed at day 2 posttransplant and increased to the time of rejection at day 7 posttransplant. IP-10 mRNA and protein production were 2.5- to 8-fold lower than Mig. Whereas allografts were rejected at day 7-9 in control recipients, treatment with rabbit antiserum to Mig, but not to IP-10, prolonged allograft survival up to day 19 posttransplant. At day 7 posttransplant, allografts from Mig antiserum-treated recipients had marked reduction in T cell infiltration. At the time of rejection in Mig antiserum-treated recipients (i.e., days 17-19), intra-allograft expression of macrophage-inflammatory protein-1alpha, -1beta, and their ligand CCR5 was high, whereas expression of CXCR3, the Mig receptor, was virtually absent. Mig was produced by the allograft endothelium as well as by recipient allograft-infiltrating macrophages and neutrophils, indicating the synergistic interactions between innate and adaptive immune compartments during acute rejection. Collectively, these results indicate that Mig is a dominant recruiting factor for alloantigen-primed T cells into cardiac allografts during acute rejection. Although Mig antagonism delays acute heart allograft rejection, the results also suggest that the alloimmune response circumvents Mig antagonism through alternative mechanisms.

Acute Disease↗
PubMed1994

Down-regulation of membrane immunoglobulin-associated proteins, MB-1, B29 and Lyn, in AIDS-lymphomas and related conditions.

B-lymphocytes infected with Epstein-Barr virus (EBV) can proliferate in immunocompromised hosts to form lymphomas (MLs). Similar MLs are produced in mice with severe combined immune deficiency (SCID) by transfusion of human lymphocytes infected with EBV (SCID-EBV-positive BML). Mb-1 and B29 are recently found transmembrane proteins associated with membrane immunoglobulins (mIg) on the surface of B cells. Lyn is a src family gene product expressed in B cells submembranously, in association with mIg, possibly through Mb-1/B29 heterodimer. These mIg-associated proteins (Mb-1, B29 and Lyn) are known to mediate antigenic stimulation through mIgs. We noted recently that Lyn is decreased selectively in around a half of SCID-EBV-positive BMLs. We extended this line of investigation to other mIg-associated proteins. Five acquired immunodeficiency syndrome (AIDS)-MLs and ten SCID-EBV-positive BMLs were first analysed by immunohistochemistry for the expression of Mb-1, B29 and Lyn. It was found that in AIDS-MLs, all the mIg-associated proteins were heavily down-regulated. In SCID-EBV-positive BMLs, Mb-1 was down regulated in six of ten, B29 in nine of ten and Lyn in six of ten, whereas no down-regulation was noted in eight EBV-free B MLs that were also maintained in SCID mice. An additional flow-cytometric study of two SCID-EBV-positive and two EBV-negative BMLs showed similar down-regulation in the former cases exclusively. Whereas mIg was also decreased in three of five SCID-EBV positive BMLs, it did not necessarily match the decrease of mIg-associated proteins, which contrasts with the recent finding that mIgs coexist with Mb-1 or B29. Some EBV-encoded proteins may activate host molecules located downwardly; this, in turn, may lead to the suppression of these upwardly-located mIg-associated proteins.

Adult↗
PubMed2000

The CXC chemokines gamma interferon (IFN-gamma)-inducible protein 10 and monokine induced by IFN-gamma are released during severe melioidosis.

Gamma interferon (IFN-gamma)-inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig) are related CXC chemokines which bind to the CXCR3 receptor and specifically target activated T lymphocytes and natural killer (NK) cells. The production of IP-10 and Mig by various cell types in vitro is strongly dependent on IFN-gamma. To determine whether IP-10 and Mig are released during bacterial infection in humans, we measured plasma levels of IP-10 and Mig in patients with melioidosis, a severe gram-negative infection caused by Burkholderia pseudomallei. IP-10 and Mig were markedly elevated in patients with melioidosis on admission, particularly in blood culture-positive patients, and remained elevated during the 72-h study period. Levels of IP-10 and Mig showed a positive correlation with IFN-gamma concentrations and also correlated with clinical outcome. In whole blood stimulated with heat-killed B. pseudomallei, neutralization of IFN-gamma and tumor necrosis factor alpha (TNF-alpha) partly attenuated IP-10 and Mig release, while anti-interleukin-12 (IL-12) and anti-IL-18 had a synergistic effect. Stimulation with other bacteria or endotoxin also induced strong secretion of IP-10 and Mig. These data suggest that IP-10 and Mig are part of the innate immune response to bacterial infection. IP-10 and Mig may contribute to host defense in Th1-mediated host defense during infections by attracting CXCR3(+) Th1 cells to the site of inflammation.

Adolescent↗