Synergy Between CD40 Ligation and IL-4 on Fibroblast Proliferation Involves IL-4 Receptor Signaling

Abstract

Fibrosis can be an undesired consequence of activated cellular immune responses. The purpose of this work was to determine whether CD40 ligation and the pro-fibrotic cytokine IL-4 interact in regulating fibroblast proliferation and collagen production, and, if so, the mechanisms used. This study found that the combination of IL-4 and ligation of CD40 on the fibroblast cell surface had synergistic effects in stimulating fibroblast proliferation. In contrast, CD40 ligation negated the inhibitory effects of IFN-γ on fibroblast proliferation. Western blotting analyses of fibroblast crude lysates revealed that a potential mechanism of the synergy between CD40 ligation and IL-4 was the phosphorylation of proteins at 130 kDa and, to a lesser degree, at 95, 85, and 75 kDa. Immunoprecipitation-Western blotting experiments showed that phosphorylation levels of IL-4Rα, Janus kinase 1, insulin receptor substrate 1, and insulin receptor substrate 2, factors with molecular mass close to the observed 130 kDa major phosphorylation band, increased in response to the combined CD40 ligation and IL-4 action. In contrast, there was no evidence that synergy was mediated by an increased expression of IL-4Rα chain, CD40, or the autocrine profibrotic cytokines IL-6 and TGF-β. These findings suggest that CD40-CD40 ligand contacts between fibroblasts and cells secreting IL-4 may promote the profibrotic effects of IL-4 by affecting signal transduction and reducing the anti-fibrotic effects of IFN-γ.

Dual Roles of IL-4 in Lung Injury and Fibrosis

“…Thus, these data from the C57BL/6 mice are consistent with a minimal, if any, direct role for IL-4 in the fibrotic response, as previously suggested (9). The basis for this lack of IL-4 responsiveness in C57BL/B6 fibroblasts remains to be determined, but may be due to possible absence of adequate and functional receptor(s) and/or synergistic activation by molecules such as CD40 ligand (51)(52)(53)(54). In addition, the fact that transgenic mice overexpressing IL-4 fail to develop significant fibrosis (6,12) may reflect an intrinsic difference in the responsiveness of murine fibroblasts to IL-4 relative to the mouse background strain used (C57BL/6).…”

Novel Model of Constrictive Pericarditis Associated With Autoimmune Heart Disease in Interferon-γ–Knockout Mice

“…18 In vitro studies have further confirmed the stimulatory effects of IL-4 and suppressive effects of IFN-␥ on fibroblast proliferation and collagen deposition. 19,20 It is therefore likely that Th2 cytokines are important for the development of fibrosis in the pericardium in EAM. Predominant Th2 responses in the absence of IFN-␥ in EAM are also demonstrated by increased numbers of eosinophils in the pericardium.…”

“…Predominant Th2 responses in the absence of IFN-␥ in EAM are also demonstrated by increased numbers of eosinophils in the pericardium. Eosinophils have been reported to participate in the development of fibrosis, 19,21 including the cardiac fibrosis associated with Loffler's endocarditis. 22 In summary, this work describes a novel model of constrictive pericarditis, associated with the typical morphological features of pericarditis and a classic constrictive physiology.…”

Study of Conjunctival Flora in Patients after Peripheral Blood Stem Cell Transplantation and its Correlation with Tear Secretion

“…[19] Mononuclear cells infiltration, adhesion molecules (CD -17) are also involved in the disease process. [4,[22][23][24][25] In addition, total body irradiation and ocular toxicity from bone marrow transplantation. [1,16,26,27] The composition of the normal human ocular surface flora had been identified, and the most prominent ocular flora includes Staphylococcus epidermidis, S. aureus, and Diphtheroids.…”