Human lung myofibroblasts as effectors of the inflammatory process: The common receptor γ chain is induced by Th2 cytokines, and CD40 ligand is induced by lipopolysaccharide, thrombin and TNF-α

Christelle Doucet, Julien Giron-Michel, Giorgio Walter Canonica, Bruno Azzarone

Research output: Contribution to journalArticle

Abstract

The common γ (γc) 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 γc chain and its association with Janus kinase (JAK) 3, while lung myofibroblasts constitutively express a γc chain displaying a limited association with JAK3. In the latter cells, without exogenous cytokines, γc/JAK3 controls, through autocrine loops, tyrosine kinase (TYK) 2 phosphorylation and the balance between functional (IL-4Rα, IL-13Rα1) and decoy (IL-13Rα2) high-affinity receptors. Moreover, JAK3 is also associated with a prephosphorylated IL-4Rα and CD40. This novel "heterotrimer" (p-IL-4Rα, 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-4Rα/IL-13Rα1/γc) 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 γc 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.

Original languageEnglish
Pages (from-to)2437-2449
Number of pages13
JournalEuropean Journal of Immunology
Volume32
Issue number9
DOIs
Publication statusPublished - Sep 2002

Fingerprint

CD40 Ligand
Myofibroblasts
Interleukin-13
Thrombin
Lipopolysaccharides
Cytokines
Lung
Phosphorylation
Janus Kinase 3
TYK2 Kinase
Interleukin-4
Asthma
Fibroblasts

Keywords

  • CD40
  • Common γ chain
  • IL-3
  • Janus kinase 3
  • Myofibroblast

ASJC Scopus subject areas

  • Immunology

Cite this

Human lung myofibroblasts as effectors of the inflammatory process : The common receptor γ chain is induced by Th2 cytokines, and CD40 ligand is induced by lipopolysaccharide, thrombin and TNF-α. / Doucet, Christelle; Giron-Michel, Julien; Canonica, Giorgio Walter; Azzarone, Bruno.

In: European Journal of Immunology, Vol. 32, No. 9, 09.2002, p. 2437-2449.

Research output: Contribution to journalArticle

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