Expression of Matrix Metalloproteinase-13 Is Controlled by IL-13 via PI3K/Akt3 and PKC-δ in Normal Human Dermal Fibroblasts

Abstract

IL-13, a T helper type 2 cytokine, is reported to be increased in the tissue of patients with atopic dermatitis (AD). In addition, chronic lichenified plaques in AD show thickened epidermis and dermis. We hypothesized that IL-13 is involved in tissue remodeling by altering the expression of matrix metalloproteinases (MMPs). In this study, we examined the MMP-related genes targeted by IL-13 in human dermal fibroblasts using a complementary DNA microarray. We focused on the MMP-13 gene, which was identified as one of the MMPs suppressed by IL-13. IL-13 downregulated both MMP-13 protein and mRNA expression. IL-13 suppressed MMP-13 expression more effectively in the presence of protein kinase C (PKC)-δ inhibitor, whereas IL-13 upregulated MMP-13 in the presence of inhibitors of phosphoinositide 3-kinase (PI3K)/Akt pathway or Akt3-specific small interfering RNA. Our results suggest that MMP-13 expression is negatively controlled by PI3K/Akt3 and positively regulated by PKC-δ in the presence of IL-13. Taken together, these findings indicate that IL-13 may induce the formation of thickened dermis in AD by decreasing collagen degradation. Blockade of IL-13 signaling cascades in AD patients may be a new therapeutic approach.

Tissue remodeling in eosinophilic esophagitis

“…IL-4 and IL-13 induce the expression of activated fibroblast markers (␣-SMA, fibronectin, CTGF), and, in human fibroblasts and stellate cells, IL-4 and IL-13 regulate the expression of matrix proteins (collagen, MMP, periostin) (9,92,105,125,151). In addition to these profibrotic effects, IL-13 and IL-4 also can induce fibroblasts to produce proinflammatory substances, including the eosinophil chemoattractant eotaxin (59,60).…”

“…2) (32). (21,57,156) ϩ ϩ ϩ ϩ TNF-␣ (24,95,113,155) ϩ ϩ ϩ ϩ ϩ ϩ VEGF (113,122) ϩ ϩ ϩ FGF-2 (16,22,113,149) ϩ ϩ ϩ ϩ ϩ ϩ PDGF (16,36,113) ϩ ϩ ϩ ϩ ϩ EGF (10,16,23,127) ϩ (17,21,92,105,151) ϩ ϩ ϩ ϩ MMP-9 (71,115) ϩ ϩ ϩ Angiogenin (122) ϩ ϩ MBP (66,108,132) ϩ ϩ ϩ ϩ Chymase (82,129) ϩ ϩ ϩ ϩ Tryptase (26,49,129,163) ϩ ϩ ϩ ϩ ϩ Histamine (5,58) ϩ ϩ ϩ Heparin (49) ϩ ϩ…”

Strategies targeting the IL-4/IL-13 axes in disease

“…IL-13 suppresses MMP-13 secretion from dermal fibroblasts, this may decrease collagen degradation and lead to dermal thickening [222]. IL-13 induces type I collagen production from primary dermal fibroblasts [223].…”

MiRNAs Mediate GDNF-Induced Proliferation and Migration of Glioma Cells

“…Recent studies have shown that Akt3 can significantly inhibit the glioma cell aggressiveness and slow down disease progression [75]. Akt3 is mainly expressed in the brain and is crucial for malignant glioma cell viability [76], which may be the key molecule in MMP13 regulation via IL13 [77]. …”