Human lung myofibroblasts as effectors of the inflammatory process: the common receptor gamma chain is induced by Th2 cytokines, and CD40 ligand is induced by lipopolysaccharide, thrombin and TNF-alpha.
The common gamma (gamma c) chain, shared by Th1 and Th2 cytokines, is fundamental for the activation of hematopoietic cells, but its role in non-hematopoietic tissues has not been explored. Here we show that in normal lung fibroblasts IL-4 and IL-13 induce the expression of the gamma c chain and ... its association with Janus kinase (JAK) 3, while lung myofibroblasts constitutively express a gamma c chain displaying a limited association with JAK3. In the latter cells, without exogenous cytokines, gamma c/JAK3 controls, through autocrine loops, tyrosine kinase (TYK) 2 phosphorylation and the balance between functional (IL-4Ralpha, IL-13Ralpha 1) and decoy (IL-13Ralpha 2) high-affinity receptors. Moreover, JAK3 is also associated with a pre-phosphorylated IL-4Ralpha and CD40. This novel "heterotrimer" (p-IL-4Ralpha, CD40/JAK3) is functional and controls STAT3 phosphorylation and CD40 expression, as shown by use of the specific JAK3 inhibitor WHI-P31. In basal culture conditions, CD40 signaling could be induced by the transient establishment of inter-fibroblastic CD40/CD40 ligand (CD40L) functional bridges. Indeed, powerful pro-inflammatory stimuli such as lipopolysaccharide and thrombin can rapidly mobilize CD40L at the surface of lung myofibroblasts. These interactions are modified by IL-13, which triggers the formation of a new type of functional receptor (p-IL-4Ralpha /IL-13Ralpha 1/gamma c) and also the recruitment and the phosphorylation of JAK3. Treatment with JAK3 inhibitors blocks IL-13-induced phosphorylation of JAK2, TYK2 and STAT3, but not of JAK1 and STAT6. These data underline (1) the pivotal role of the gamma c chain, CD40/CD40L, JAK3 and IL-13 in the inflammatory-like activation of lung myofibroblasts, (2) the cell-type restraint effects of IL-13 on these cells, and (3) the potential usefulness of JAK3 inhibitors in the treatment of asthma.
Mesh Terms:
Anti-Asthmatic Agents, Antigens, CD40, Autocrine Communication, CD40 Ligand, Cells, Cultured, DNA-Binding Proteins, Drug Design, Fibroblasts, Gene Expression Regulation, Humans, Inflammation, Interleukin Receptor Common gamma Subunit, Interleukin-13, Interleukin-13 Receptor alpha1 Subunit, Interleukin-4, Janus Kinase 2, Janus Kinase 3, Lipopolysaccharides, Lung, Macromolecular Substances, Phosphorylation, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptors, Interleukin, Receptors, Interleukin-13, Receptors, Interleukin-4, Receptors, Interleukin-7, Recombinant Fusion Proteins, STAT3 Transcription Factor, Signal Transduction, TYK2 Kinase, Thrombin, Trans-Activators, Tumor Necrosis Factor-alpha
Anti-Asthmatic Agents, Antigens, CD40, Autocrine Communication, CD40 Ligand, Cells, Cultured, DNA-Binding Proteins, Drug Design, Fibroblasts, Gene Expression Regulation, Humans, Inflammation, Interleukin Receptor Common gamma Subunit, Interleukin-13, Interleukin-13 Receptor alpha1 Subunit, Interleukin-4, Janus Kinase 2, Janus Kinase 3, Lipopolysaccharides, Lung, Macromolecular Substances, Phosphorylation, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptors, Interleukin, Receptors, Interleukin-13, Receptors, Interleukin-4, Receptors, Interleukin-7, Recombinant Fusion Proteins, STAT3 Transcription Factor, Signal Transduction, TYK2 Kinase, Thrombin, Trans-Activators, Tumor Necrosis Factor-alpha
Eur. J. Immunol.
Date: Sep. 01, 2002
PubMed ID: 12207328
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