Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Notch signaling pathways exert diverse biological effects depending on the cellular context where Notch receptors are activated. How Notch signaling is integrated with environmental cues is a central issue. Here, we show that Notch activation accelerates ubiquitin-mediated and mitogen-activated protein kinase (MAPK)-dependent degradation of E2A transcription factors and Janus kinases, molecules essential for both B- and T-lymphocyte development. However, these events occur in B lymphocytes, but not T lymphocytes, due to their different levels of MAPK, thus providing one mechanism whereby Notch inhibits B-cell development without impairing T-cell differentiation. Lymphoid progenitors expressing a Notch-resistant E2A mutant differentiated into B-lineage cells on stromal cells expressing Notch ligands and in the thymus of transplant recipients. Bone marrow transplant assays and examination of steady-state B lymphopoiesis also revealed that the expression of Notch-resistant E2A and constitutively active STAT5 in mice neutralized the effects of Notch-induced degradation, allowing B-cell development through a bone marrow-like program in the thymus. These findings illustrate that Notch function can be influenced by MAPKs, producing distinct outcomes in different cellular contexts.
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PMID:Regulation of lymphocyte development by cell-type-specific interpretation of Notch signals. 1819 39

RasGRP1 and Sos are two Ras-guanyl-nucleotide exchange factors that link TCR signal transduction to Ras and MAPK activation. Recent studies demonstrate positive selection of developing thymocytes is crucially dependent on RasGRP1, whereas negative selection of autoreactive thymocytes appears to be RasGRP1 independent. However, the role of RasGRP1 in T regulatory (Treg) cell development and function is unknown. In this study, we characterized the development and function of CD4(+)CD25(+)Foxp3(+) and CD8(+)CD44(high)CD122(+) Treg lineages in RasGRP1(-/-) mice. Despite impaired CD4 Treg cell development in the thymus, the periphery of RasGRP1(-/-) mice contained significantly increased frequencies of CD4(+)Foxp3(+) Treg cells that possessed a more activated cell surface phenotype. Furthermore, on a per cell basis, CD4(+)Foxp3(+) Treg cells from mutant mice are more suppressive than their wild-type counterparts. Our data also suggest that the lymphopenic environment in the mutant mice plays a dominant role of favored peripheral development of CD4 Treg cells. These studies suggest that whereas RasGRP1 is crucial for the intrathymic development of CD4 Treg cells, it is not required for their peripheral expansion and function. By contrast to CD4(+)CD25(+)Foxp3(+) T cells, intrathymic development of CD8(+)CD44(high)CD122(+) Treg cells is unaffected by the RasGRP1(-/-) mutation. Moreover, RasGRP1(-/-) mice contained greater numbers of CD8(+)CD44(high)CD122(+) T cells in the spleen, relative to wild-type mice. Activated CD8 Treg cells from RasGRP1(-/-) mice retained their ability to synthesize IL-10 and suppress the proliferation of wild-type CD8(+)CD122(-) T cells, albeit at a much lower efficiency than wild-type CD8 Treg cells.
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PMID:Preferential development of CD4 and CD8 T regulatory cells in RasGRP1-deficient mice. 1842 17

Thymic selection is a tightly regulated developmental process essential for establishing central tolerance. The intensity of TCR-mediated signaling is a key factor for determining cell fate in the thymus. It is widely accepted that low-intensity signals result in positive selection, whereas high-intensity signals induce negative selection. Transmembrane adaptor proteins have been demonstrated to be important regulators of T cell activation. However, little is known about their role during T cell development. Herein, we show that SIT (SHP2 Src homology domain containing tyrosine phosphatase 2-interacting transmembrane adaptor protein) and TRIM (TCR-interacting molecule), two structurally related transmembrane adaptors, cooperatively regulate TCR signaling potential, thereby influencing the outcome of thymic selection. Indeed, loss of both SIT and TRIM resulted in the up-regulation of CD5, CD69, and TCRbeta, strong MAPK activation, and, consequently, enhanced positive selection. Moreover, by crossing SIT/TRIM double-deficient mice onto transgenic mice bearing TCRs with different avidity/affinity, we found profound alterations in T cell development. Indeed, in female HY TCR transgenic mice, positive selection was completely converted into negative selection resulting in small thymi devoided of double-positive thymocytes. More strikingly, in a nonselecting background, SIT/TRIM double-deficient single-positive T cells developed, were functional, and populated the periphery. In summary, we demonstrated that SIT and TRIM regulate cell fate of developing thymocytes, thus identifying them as essential regulators of central tolerance.
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PMID:SIT and TRIM determine T cell fate in the thymus. 1894 Nov 81

Regain of immunocompetence after myeloablation and bone marrow cell (BMC) reconstitution essentially depends on T progenitor homing into the thymus and intrathymic T cell maturation. CD44 facilitates progenitor homing and settlement in the bone marrow and is known as a T progenitor marker. In search for improving regain of immunocompetence after BMC reconstitution, we explored whether the CD44 standard (CD44 s) and/or variant isoforms CD44v6 and CD44v7 contribute to thymus repopulation and thymocyte maturation. Antibody-blocking studies and cells/mice with a targeted deletion of CD44v6/7 or CD44v7 revealed that CD44s, but not CD44v6 and CD44v7, has a major impact on progenitor cell homing into the thymus. Instead, CD44v6 strengthens apoptosis resistance and expansion of early thymocytes. CD44v6-induced apoptosis resistance, most strong in double-negative (DN) thymocytes, is accompanied by Akt activation. CD44v6-induced proliferation of DN cells proceeds via activation of the MAPK pathway. At later stages of T cell maturation, CD44 acts as an accessory molecule, initiating and supporting TCR/CD3 complex-mediated signal transduction in double-positive and single-positive thymocytes. Thus, CD44 plays a major role in thymus homing. In addition, CD44v6 is important for survival and expansion of early thymocytes. These findings suggest that strengthening CD44v6 expression on lymphoid progenitors could well contribute to accelerated regain of immunocompetence.
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PMID:CD44 promotes progenitor homing into the thymus and T cell maturation. 1895 44

Reactivity to self-peptide/MHC complexes is required for selection of the TCR repertoire in the thymus but can also promote autoimmunity. Reduced TCR sensitivity of mature T cells is thought to help control the autoreactivity in peripheral T cells. The molecular basis for reduced sensitivity of peripheral T cells is not known. We found that peripheral T cells, but not immature thymocytes, lacking IFN-gamma-inducible lysosomal thiol reductase (GILT) display increased sensitivity to TCR ligation. GILT-/- peripheral T cells express reduced levels of mitochondrial superoxide dismutase 2 and consequently display higher levels of reactive oxygen radicals and ERK1/2 phosphorylation following activation. The increased sensitivity of GILT-deficient T cells results in a more severe hyperglycemia associated with streptozotocin-induced diabetes. GILT expression levels progressively increase in T cells with maturation. These data suggest that regulation of GILT expression may be a mechanism of T cell differentiation-associated changes in sensitivity to TCR engagement.
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PMID:Cutting edge: developmental up-regulation of IFN-gamma-inducible lysosomal thiol reductase expression leads to reduced T cell sensitivity and less severe autoimmunity. 1912 16

Perfluorononanoate (PFNA), a perfluorinated alkyl acid containing nine carbon chains, has been detected in abiotic and biotic matrices worldwide. Although a few studies have reported toxic effects of PFNA, little information of the mechanism has been offered. In this study, the effects of PFNA exposure on thymus and the related mechanisms were investigated. Male rats were orally dosed with 0, 1, 3, or 5 mg PFNA/kg/day for 14 days. A significant decrease of body weight and thymus weight were observed in the rats receiving 3 or 5 mg PFNA/kg/day. Histopathological examination revealed dose-dependent increases in thymocyte apoptosis. Rats receiving 3 or 5 mg PFNA/kg/day exhibited increased interleukin (IL)-1 and decreased IL-2 concentrations in sera, whereas elevated IL-4 and cortisol levels only occurred in the highest dose group. Quantitative real-time PCR indicated that expression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) was increased in the thymi of all dosed rats, and a similar trend occurred for PPAR-gamma in the two highest dose groups. The mRNA levels of c-Jun NH(2)-terminal kinase (JNK), nuclear factor-kappa B, p65 subunit, and inhibitory protein IkappaBalpha were unchanged; however, increased and decreased mRNA levels of p38 kinase were found in rats exposed to 3 or 5 mg PFNA/kg/day, respectively. Decreased Bcl-2 mRNA levels were observed in rats receiving 5 mg PFNA/kg/day. A significant increase in protein levels of phospho-JNK was found in all PFNA-treated rats. Phospho-p38 was significantly enhanced in 1 and 3 mg PFNA/kg/day groups, whereas phospho-IkappaBalpha remained consistent in all rats studied. Together, these data suggested that apart from the activation of PPARs, PFNA exposure in rats lead to the alteration of serum cytokines, which subsequently activated mitogen-activated protein kinase signaling pathways and potentially modulated the immune system. Additionally, increased serum cortisol and decreased expression of Bcl-2 in thymus likely contributed to the PFNA-induced thymocyte apoptosis.
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PMID:Alterations of cytokines and MAPK signaling pathways are related to the immunotoxic effect of perfluorononanoic acid. 1919 29

Ouabain, a known inhibitor of the Na,K-ATPase, has been shown to regulate a number of lymphocyte functions in vitro and in vivo. Lymphocyte proliferation, apoptosis, cytokine production, and monocyte function are all affected by ouabain. The ouabain-binding site occurs at the alpha subunit of the enzyme. The alpha subunit plays a critical role in the transport process, and four different alpha-subunit isoforms have been described with different sensitivities to ouabain. Analysis by RT-PCR indicates that alpha1, alpha2, and alpha3 isoforms are all present in murine lymphoid cells obtained from thymus, lymph nodes, and spleen. In these cells ouabain exerts an effect at concentrations that do not induce plasma membrane depolarization, suggesting a mechanism independent of the classical inhibition of the pump. In other systems, the Na,K-ATPase acts as a signal transducer in addition to being an ion pump, and ouabain is capable of inducing the activation of various signal transduction cascades. Neither resting nor concanavalin A (Con A)-activated thymocytes had their levels of phosphorylated-extracellular signal-regulated kinase (P-ERK) modified by ouabain. However, ouabain decreased p38 phosphorylation induced by Con A in these cells. The pathway induced by ouabain in lymphoid cells is still unclear but might vary with the type and state of activation of the cell.
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PMID:Modulation of the immune system by ouabain. 1923 38

Tec family kinases are important components of antigen receptor signaling pathways in B cells, T cells, and mast cells. In T cells, three members of this family, inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk), and Tec, are expressed. In the absence of Itk and Rlk, T-cell receptor signaling is impaired, with defects in mitogen-activated protein kinase activation, Ca(2+) mobilization, and actin polymerization. During T-cell development in the thymus, no role has been found for these kinases in the CD4(+) versus CD8(+) T-cell lineage decision; however, several studies indicate that Itk and Rlk contribute to the signaling leading to positive and negative selection. In addition, we and others have recently described an important role for Itk and Rlk in the development of conventional as opposed to innate CD4(+) and CD8(+) T cells. Natural killer T and gammadelta T-cell populations are also altered in Itk- and Rlk/Itk-deficient mice. These findings strongly suggest that the strength of T-cell receptor signaling during development determines whether T cells mature into conventional versus innate lymphocyte lineages. This lineage decision is also influenced by signaling via signaling lymphocytic activation molecule (SLAM) family receptors. Here we discuss these two signaling pathways that each contribute to conventional versus innate T-cell lineage commitment.
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PMID:The Tec kinases Itk and Rlk regulate conventional versus innate T-cell development. 1929 Sep 24

Depletion of T-cell-dependent immunity is a major consideration for patients suffering from infections of human immunodeficiency virus (HIV), those undergoing organ transplantation, and those receiving anti-cancer chemotherapy and/or radiotherapy. In general, T-cell regeneration occurs in the thymus through thymopoiesis. We have found that doxycycline (Dox), a tetracycline derivative, enhances the proliferation of mouse thymic epithelial cells, which are unique in their capacity to support positive selection and are essential throughout the development of thymocytes. Cell cycle analysis indicates that the increased cell proliferation is due to a shortened G(0)/G(1) phase. To reveal the underlying mechanisms, we examined the expression of an array of molecules that regulate the cell cycle. The results show that in mouse thymic medullary-type epithelial cell line 1 (MTEC1) Dox leads to elevated levels of H-Ras, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), cyclin E, cyclin dependent kinase 4/2 (CDK4/CDK2), E2F3, and c-myc. These data, and the observation that the proliferation-enhancing effect is largely abolished following treatment with an ERK inhibitor support an active role of the Ras-ERK/mitogen-activated protein kinase (MAPK) signaling pathway. In conclusion, the present study reveals a new activity of an old family of antibiotics. The in vivo effect of Dox on immune reconstitution warrants further exploration.
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PMID:Doxycycline enhances the Ras-MAPK signaling and proliferation of mouse thymic epithelial cells. 1933 Aug 5

Galectin (Gal) constitute a family of carbohydrate-recognizing molecules ubiquitously expressed in mammals. In the immune system, they regulate many processes such as inflammation, adhesion, and apoptosis. Here, we report the expression in the spleen of the two same Gal-8 splice variants described previously in the thymus. Gal-8 was found to induce two separate biological activities on T lymphocytes: a robust naive CD4(+) T cell proliferation in the absence of antigen and notably, a costimulatory signal that synergized the cognate OVA peptide in DO11.10 mice transgenic for TCR(OVA). The antigen-independent proliferation induced by Gal-8 displayed increased expression of pro- and anti-inflammatory cytokines, thus suggesting the polyclonal expansion of Th1 and Th2 clones. The costimulatory effect on antigen-specific T cell activation was evidenced when the Gal and the peptide were assayed at doses suboptimal to induce T cell proliferation. By mass spectra analysis, several integrins and leukocyte surface markers, including CD45 isoforms, as well as other molecules specific to macrophages, neutrophils, and platelets, were identified as putative Gal-8 counter-receptors. Gal-8 triggered pZAP70 and pERK1/2. Moreover, pretreatment with specific inhibitors of CD45 phosphatase or ERK1/2 prevented its antigen-dependent and -independent T cell-proliferative activities. This seems to be associated with the agonistic binding to CD45, which lowers the activation threshold of the TCR signaling pathway. Taken together, our findings support a distinctive role for locally produced Gal-8 as an enhancer of otherwise borderline immune responses and also suggest that Gal-8 might fuel the reactivity at inflammatory foci.
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PMID:Galectin-8 provides costimulatory and proliferative signals to T lymphocytes. 1940 94


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