Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways.
Thymic stromal lymphopoietin (TSLP) plays a pivotal role in allergic diseases such as asthma, chronic obstructive pulmonary disease, and atopic dermatitis. Enhanced TSLP expression has been detected in asthmatic airways that correlated with both the expression of Th2-attracting chemokines and with disease severity. Although cumulative evidence suggests that human airway smooth muscle (HASM) cells can initiate or perpetuate the airway inflammation by secreting a variety of inflammatory cell products such as cytokines and chemokines, the role of TSLP in this pathway is not known. In the current study, we sought to investigate whether HASM cells express the TSLP receptor (TSLPR) and whether it is functional. We first demonstrated that primary HASM cells express the transcript and protein of both TSLPR subunits (TSLPR and IL-7Ralpha). Functionally, TSLPR-mediated HASM activation induced a significant increase in CXC (IL-8/CXCL8), CC (eotaxin-1/CCL11) chemokines, and proinflammatory cytokine IL-6 expression. Furthermore, using biochemical and genetic approaches, we found that TSLP-induced proinflammatory gene expression in HASM involved the transcriptional mechanisms, MAPKs (ERK1/2, p38, and JNK), and STAT3 activation. Finally, TSLPR immunoreactivity in bronchial sections from mild allergic asthmatics suggested the potential in vivo TSLP targeting of HASM. Altogether, our data suggest that the TSLPR-mediated HASM activation induces proinflammatory cytokine and chemokines release that may facilitate inflammatory immune cells recruitment in airways. In addition, it may be inferred that TSLPR is involved in the pathogenesis of allergic asthma through the activation of HASM cells by TSLP.
Shan
Lianyu
L
Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Redhu
Naresh Singh
NS
Saleh
Ali
A
Halayko
Andrew J
AJ
Chakir
Jamila
J
Gounni
Abdelilah S
AS
D002469:Cell Separation; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000276:immunology; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000276:immunology / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
C498762:CRLF2 protein, human; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016207:Cytokines; D015850:Interleukin-6; D018121:Receptors, Cytokine; D050796:STAT3 Transcription Factor; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D000094632:Thymic Stromal Lymphopoietin