Implication of Interleukin-4 in Wound Healing

Salmon-Ehr, V; Ramont, Laurent; Godeau, Gaston; Birembaut, Philippe; Guenounou, Moncef; Bernard, Philippe; Maquart, François‐Xavier

doi:10.1038/labinvest.3780141

Cited by 119 publications

(80 citation statements)

References 19 publications

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“…A previous report demonstrated that topical administration of IL-4 significantly accelerated wound healing, whereas IL-4 antisense oligonucleotides significantly inhibited healing. 26 By contrast, IL-10 is an inhibitory factor for the remodeling of extracellular matrix during wound healing. 40 Addition of a neutralizing anti-IL-10 Ab inhibits the infiltration of neutrophils and macrophages toward the wound.…”

Section: 32mentioning

confidence: 99%

Inducible Costimulator (ICOS) and ICOS Ligand Signaling Has Pivotal Roles in Skin Wound Healing via Cytokine Production

Maeda

Fujimoto

Matsushita

et al. 2011

The American Journal of Pathology

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Section: 32mentioning

confidence: 99%

Inducible Costimulator (ICOS) and ICOS Ligand Signaling Has Pivotal Roles in Skin Wound Healing via Cytokine Production

Maeda

Fujimoto

Matsushita

et al. 2011

The American Journal of Pathology

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“…Exposure to IL-4 leads to an increase in collagen production in the lungs (4,13), and correlates with the amount of hepatic fibrosis (14). Normal wound healing is accelerated by IL-4 (2,15). Treatment with anti-IL-4 and the targeted mutation of IL-4R␣ prevent dermal fibrosis in the tight-skin mouse model of scleroderma (16,17).…”

mentioning

confidence: 99%

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

Atamas

Luzina

Dai

et al. 2002

The Journal of Immunology

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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.

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“…IL-4 is known to be a fibrogenic cytokine that promotes biogenesis of ECM proteins in normal wound healing and in pathological fibrosis (7,54). The present findings potentially have important clinical implications in dermal wound healing and many fibrotic diseases.…”

Section: Discussionmentioning

confidence: 88%

IL-4 Up-Regulates the Expression of Tissue Inhibitor of Metalloproteinase-2 in Dermal Fibroblasts Via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

Ihn

Yamane

Asano

et al. 2002

The Journal of Immunology

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Tissue inhibitor of metalloproteinase-2 (TIMP-2) is a potent inhibitor of activated matrix metalloproteinases such as gelatinase and collagenase, and thus helps to control extracellular matrix metabolism and deposition by connective tissue cells. We examined the responsiveness of the expression of TIMP-2 to various cytokines in dermal fibroblasts and studied the regulatory and signaling mechanisms of the response. TIMP-2 protein and mRNA expression was induced by IL-4 in a dose- and time-dependent manner, but not by TGF-β, oncostatin M, or IL-6. IL-4 induction of TIMP-2 expression was dependent upon transcription. The p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 suppressed IL-4-induced TIMP-2 expression, suggesting the involvement of p38 MAP kinase in the signaling of IL-4 leading to TIMP-2 expression. Immunoblotting analysis using a specific Ab against phosphorylated p38 MAP kinase (Thr180/Tyr182) showed that IL-4 induced phosphorylation of p38 MAP kinase in human dermal fibroblasts. Furthermore, the p38 MAP kinase assay showed that IL-4 induces p38 MAPK activation in human dermal fibroblasts. The expression of the dominant-negative mutant p38 MAPK represses the IL-4-induced TIMP-2 expression in human dermal fibroblasts. Thus, IL-4 can potentially alter the dermal matrix metabolism by regulating TIMP-2.

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Implication of Interleukin-4 in Wound Healing

Cited by 119 publications

References 19 publications

Inducible Costimulator (ICOS) and ICOS Ligand Signaling Has Pivotal Roles in Skin Wound Healing via Cytokine Production

Inducible Costimulator (ICOS) and ICOS Ligand Signaling Has Pivotal Roles in Skin Wound Healing via Cytokine Production

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

IL-4 Up-Regulates the Expression of Tissue Inhibitor of Metalloproteinase-2 in Dermal Fibroblasts Via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

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