Selective Induction of Eotaxin Release by Interleukin-13 or Interleukin-4 in Human Airway Smooth Muscle Cells Is Synergistic with Interleukin-1 β and Is Mediated by the Interleukin-4 Receptor α -Chain

Abstract

The biologic activities of interleukin (IL)-13 and IL-4 often overlap, and evidence supports their importance in atopic disease and airways hyperresponsiveness. Here, their capacity to release eosinophil-activating cytokines was examined in cultured human airway smooth muscle. IL-13 and IL-4 induced selective release of eotaxin with no effect on granulocyte-macrophage colony-stimulating factor, regulated upon activation, normal T-cell expressed and secreted (RANTES), or IL-8. A profound synergistic increase in eotaxin release occurred when IL-13 or IL-4 was combined with IL-1beta that was abrogated by a neutralizing antibody to the IL-4 receptor alpha (IL-4Ralpha)-chain but not to the IL-2 receptor gamma (IL-2Rgamma)-chain. Expression of cell surface IL-4 receptors and IL-4Ralpha in lysates was constitutive and unchanged by treatment with IL-13 or IL-4 alone or in combination with IL-1beta. Activation of IL-4Ralpha by IL-13 or IL-4 induced signal transducer and activation of transcription-6 (STAT6), p42/ p44 ERK, p38, and to a lesser extent, SAPK/JNK mitogen-activated protein kinase phosphorylation. STAT6 and MAP kinase activation by IL-13 or IL-4 was not further potentiated after combined stimulation with IL-1beta. However, eotaxin release induced by IL-13 or IL-4 alone, and in combination with IL-1beta, was prevented by the MEK inhibitor U 0126 and by the p38 inhibitor SB 202190. Collectively, the data suggest that selective eotaxin release induced either by IL-13 and IL-4 or when combined with IL-1beta is mediated by a constitutive cell surface IL-4Ralpha and the activation of multiple intracellular pathways.

Matrix Metalloproteinase-9 Deficiency Results in Enhanced Allergen-Induced Airway Inflammation

“…This effect was specific to eotaxin and MDC, as no increase in levels of other chemokines important during allergen-induced airway inflammation, MCP-1/ CCL2, MIP-1␣/CCL3, and RANTES/CCL5 was observed (data not shown). It is also possible that MMP-9 has a direct effect on Th2 cytokine generation, and because both IL-4 and IL-13 directly contribute to generation of eotaxin and MDC this would promote recruitment of eosinophils and Th2 cells (25,26), while increased IL-5 would enhance eosinophil survival (27). Recently, it has been demonstrated that IL-5 can down-modulate its receptor, thereby limiting IL-5-dependent inflammatory conditions.…”

A stage‐specific functional role of the leucine zipper transcription factor c‐Maf in lung Th2 cell differentiation

“…This is consistent with the increased number and activation state of eosinophils through IL-5 receptor signaling in the airways of c-maf-Tg mice. The interactions of eosinophils and bronchial epithelial cells are important for the development of asthma and are mediated by chemokines like cationic granule proteins, MBP, eosinophilic cationic protein (ECP) derived from eosinophils, and eotaxin derived from bronchial epithelial cells after challenge with IL-13 [4,5,[27][28][29]. However, upon OVA sensitization, c-maf-Tg mice showed in fact reduced IL-5 production as compared to wild-type mice, suggesting stage-specific effects of c-Maf overexpression on IL-5 and Th2 cytokine production by lung T cells.…”

“…This concept was confirmed by studies on isolated CD4 + T lymphocytes from the lungs of c-maf-Tg mice, showing that overexpression of c-Maf augments IL-5 production early, but not late, under Th2-skewing conditions. IL-13 is a cytokine known to induce airway inflammation, AHR and mucus production [24,25,[28][29][30]. Activation of both IL-13 and IL-4 membrane-bound heterodimeric receptors induces receptor molecule dimerization and activation of the Janus family members of inner membrane-bound tyrosine kinases, which then phosphorylate and initiate the nuclear transport of STAT-6 transcription factors [9].…”

The high-affinity IgE receptor (FcεRI): a critical regulator of airway smooth muscle cells?

“…A selective eotaxin-1/CCL11 release from ASM cells has been demonstrated on IL-13 and IL-4 stimulation (50). The ultimate suggestion is that Fc⑀RI cross-linking can induce IL-4 and IL-13 release, which in turn by an autocrine pathway leads to eotaxin-1/CCL11 and IL-5 release from ASM cells.…”