p38 MAPK is a critical regulator of the constitutive and theβ4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells (original) (raw)
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European journal of immunology, 2003
Cytokines and adhesion receptors are key mediators in the dialog occurring between thymic epithelial cells (TEC) and thymocytes and regulating T cell maturation and epithelial embryonic differentiation. Among cytokines, IL-6 can be critical in the thymus, fostering proliferation, differentiation and/or survival of both TEC and thymocytes. We have previously reported in human normal TEC that clustering of the laminin receptor alpha6beta4 integrin induced by thymocyte contact or monoclonal antibody-mediated cross-linking regulates IL-6 gene expression via activation of NF-kappaB and NF-IL6 transactivators. Here we show that alpha6beta4 integrin activates p38 mitogen-activated protein kinase (MAPK) and that p38 is essential for IL-6 gene expression. In fact, beta4 cross-linking activated p38 and extracellular signal-regulated kinase (ERK) MAPK, Rac1, p21-activated protein kinase 1 (PAK1) and MAPK kinases (MKK) 3/MKK6. However, pharmacological blockade of p38 or ERK demonstrated that p3...
Developmental Immunology, 2000
T cell precursors homed to thymus develop in close contact with stromal cells. Among them, thymic epithelial cells (TEC) are known to exert dominant roles in their survival and functional shaping. Key molecules mediating TEC/thymocytes interactions include cytokines and growth factors secreted by the two cell types and adhesion receptors mediating cell contact. Signaling events triggered in thymocytes by adhesion to epithelial cells have been extensively investigated, whereas little is known on the opposite phenomenon. We have previously investigated this issue in a co-culture system composed of TEC cultures derived from human normal thymus and heterologous thymocytes. We demonstrated that thymocytes adhere to TEC involving [ and [34 integrins and induce the clustering of (z3[ and 6134 heterodimers at the TEC surface. In addition thymocyte adhesion was followed by activation of NF-zB and NF-IL6 gene transciption factors and enhanced IL-6 production. The two latter phenomena were reproduced by the cross-linking of the 3, 6, [31 and [34 integrins, thus implying that the 3131 and z6134 heterodimers can signal during thymocyte adhesion. We have extended our previous work investigating in the same experimental setting the inducing activity of non stimulated or activated policlonal or clonal mature T cells as representative of the more mature thymocyte subset. We found that adhesion of unstimulated T cell i) involved 1, but not 4 integrin functions at the surface ii) induced the clustering of 3[31, but not c21 heterodimers at the TEC surface and iii) up-regulated the nuclear binding activity of NF-r,B transcription factor and the IL-6 secretion. We propose that 31 and 64 heterodimers are induced to cluster at the TEC surface recognizing yet unknown cellular ligands differentially expressed during T cell development.
Blood, 1998
T-cell precursors develop within the thymus in contact with multiple supportive elements, among which thymic epithelial cells (TEC) are known to exert a dominant role in their homing, survival, and functional differentiation. All these functions are supported by cell-cell contacts and cytokine release. Signaling events triggered in lymphoid cells by adhesion to TEC are well characterized, but little is known about the opposite phenomenon. To address this issue, we derived cultures of TEC from human normal thymus. TEC monolayers were cocultured with thymocytes and immunostained with monoclonal antibodies (MoAbs) to integrin (2, 3, 4, and 6) and β (β1 and β4) chains. Optical and confocal analysis showed that integrins were polarized on TEC at discrete surface locations: 6β4 lined the basal surface of TEC monolayers, whereas 3β1 was found mostly at TEC-TEC contacts; it is noteworthy that both 3β1 and 6β4 became highly enriched also at the boundaries with adherent thymocytes. ...
Blood, 1998
T-cell precursors develop within the thymus in contact with multiple supportive elements, among which thymic epithelial cells (TEC) are known to exert a dominant role in their homing, survival, and functional differentiation. All these functions are supported by cell-cell contacts and cytokine release. Signaling events triggered in lymphoid cells by adhesion to TEC are well characterized, but little is known about the opposite phenomenon. To address this issue, we derived cultures of TEC from human normal thymus. TEC monolayers were cocultured with thymocytes and immunostained with monoclonal antibodies (MoAbs) to integrin (2, 3, 4, and 6) and beta (beta1 and beta4) chains. Optical and confocal analysis showed that integrins were polarized on TEC at discrete surface locations: 6beta4 lined the basal surface of TEC monolayers, whereas 3beta1 was found mostly at TEC-TEC contacts; it is noteworthy that both 3beta1 and 6beta4 became highly enriched also at the boundaries with adherent t...
The Journal of …, 2005
Myasthenia gravis (MG) is an autoimmune disease of neuromuscular junctions where thymus plays a pathogenetic role. Thymectomy benefits patients, and thymic hyperplasia, a lymphoid infiltration of perivascular spaces becoming site of autoantibody production, is recurrently observed. Cytokines and chemokines, produced by thymic epithelium and supporting survival and migration of T and B cells, are likely to be of great relevance in pathogenesis of thymic hyperplasia. In thymic epithelial cell (TEC) cultures derived "in vitro" from normal or hyperplastic age-matched MG thymuses, we demonstrate by gene profiling analysis that MG-TEC basally overexpress genes coding for p38 and ERK1/2 MAPKs and for components of their signaling pathways. Immunoblotting experiments confirmed that p38 and ERK1/2 proteins were overexpressed in MG-TEC and, in addition, constitutively activated. Pharmacological blockage with specific inhibitors confirmed their role in the control of IL-6 and RANTES gene expression. According to our results, IL-6 and RANTES levels were abnormally augmented in MG-TEC, either basally or upon induction by adhesion-related stimuli. The finding that IL-6 and RANTES modulate, respectively, survival and migration of peripheral lymphocytes of myasthenic patients point to MAPK transcriptional and posttranscriptional abnormalities of MG-TEC as a key step in the pathological remodelling of myasthenic thymus.
A Novel Integrin Involved in Thymocyte-Thymic
Summary Thymocytes differentiate in the thymic microenvironment into immunocompetent T cell through the interaction with a variety of accessory cells, including thymic epithelial cells (TEC) . TEC play an important role in the selection process presenting self antigens in association with major histocompatibilitycomplex(MHC) molecules to the maturingT cells . TheT cell receptor recognizes the selfantigen-MHC complex, but other surface molecules help stabilize this interaction. Thus, the CD2/LFA3 and LFA-1/intercellular adhesion molecule 1 pairs have been shown to participate in the binding between lymphoid cells and TEC. Here we describe an integrin of the very late activation antigen subfamily composed by the known Nt chain and by a novel ci chain. This adhesion molecule is expressed on the surface of medullary TEC and is involved in the adhesion between TEC and thymocytes, but not peripheral blood T lymphocytes.
The Journal of Immunology, 2005
Myasthenia gravis (MG) is an autoimmune disease of neuromuscular junctions where thymus plays a pathogenetic role. Thymectomy benefits patients, and thymic hyperplasia, a lymphoid infiltration of perivascular spaces becoming site of autoantibody production, is recurrently observed. Cytokines and chemokines, produced by thymic epithelium and supporting survival and migration of T and B cells, are likely to be of great relevance in pathogenesis of thymic hyperplasia. In thymic epithelial cell (TEC) cultures derived "in vitro" from normal or hyperplastic age-matched MG thymuses, we demonstrate by gene profiling analysis that MG-TEC basally overexpress genes coding for p38 and ERK1/2 MAPKs and for components of their signaling pathways. Immunoblotting experiments confirmed that p38 and ERK1/2 proteins were overexpressed in MG-TEC and, in addition, constitutively activated. Pharmacological blockage with specific inhibitors confirmed their role in the control of IL-6 and RANTES gene expression. According to our results, IL-6 and RANTES levels were abnormally augmented in MG-TEC, either basally or upon induction by adhesion-related stimuli. The finding that IL-6 and RANTES modulate, respectively, survival and migration of peripheral lymphocytes of myasthenic patients point to MAPK transcriptional and posttranscriptional abnormalities of MG-TEC as a key step in the pathological remodelling of myasthenic thymus. The Journal of Immunology, 2005, 175: 7021-7028.
Expression of functionally active alpha4beta1 integrin by thymic epithelial cells
Clinical and Experimental Immunology, 1996
We have investigated the expression and function of the VLA-4 heterodimer ® 4¯1 , a member of the¯1 integrin subfamily, on human thymic epithelial cells (TEC) derived from cortical epithelium. The expression of the ® 4 integrin chain was studied in four different cloned TEC lines derived from either fetal or post-natal human thymus by both flow cytometry and immunoprecipitation techniques with anti-® 4 MoAbs. All different cell lines assayed expressed significant levels of ® 4 , as revealed by their reactivity with MoAbs specific for distinct ® 4 epitopes. The ® 4 subunit expressed by TEC was associated to¯1 but not to¯7 chain, and displayed the characteristic 80/70 kD pattern of proteolytic cleavage. The VLA-4 integrin in these cells was constitutively active in terms of adhesiveness to both fibronectin and vascular cell adhesion molecule-1 (VCAM-1). In addition, this heterodimer localized to punctate regions of the cell in the area of contact with the substratum, named point contacts assessed by staining with the anti-¯1 activation epitope 15/7 MoAb. According to the cortical origin of the TEC lines expressing VLA-4, human thymus sections stained with different anti-® 4 antibodies revealed the presence of cortical, and in smaller numbers medullary epithelial cells bearing ® 4 integrin. The expression of ® 4 in the thymus was also found in both adult and fetal rats, in which epithelial cells were also specifically stained. Altogether, our data show that VLA-4 is an additional component of the integrin repertoire of TEC, and suggest that it could have an important role in thymus epithelial cellthymocyte interactions.
Signaling Pathways Leading to the Activation of IKK and MAPK by Thymosin 1
Annals of the New York Academy of Sciences, 2007
Thymosin alpha 1 (T␣1) has therapeutic potential in the treatment of infectious diseases and cancer. However, the exact molecular pathways for T␣1 action are not fully understood. We found that T␣1 induces the production of interleukin-6 (IL-6), IL-10, and IL-12 in murine bone marrow-derived macrophages (BMDMs) through IKK and MAPK pathways. T␣1 triggers the activation of AP-1 and the phosphorylation of JNK and p38. Inhibition of p38 impairs IL-6 production in response to T␣1. Further, TRAF6 is involved in the activation of JNK and IRAK4 is involved for the activation of IKK and PKC in a T␣1induced system. Loss of IRAK4 largely blocked induction of IL-6. Thus, our studies define early signal events that are critical for the T␣1-induced immune responses.