Proinflammatory role of amphiregulin, an epidermal growth factor family member whose expression is augmented in rheumatoid arthritis patients

Abstract

Background: The epidermal growth factor (EGF) and EGF receptor (EGFR) families play important roles in the hyperplastic growth of several tissues as well as tumor growth. Since synovial hyperplasia in rheumatoid arthritis (RA) resembles a tumor, involvement of the EGF/EGFR families in RA pathology has been implied. Although several reports have suggested that ErbB2 is the most important member of the EGFR family for the synovitis in RA, it remains unclear which members of the EGF family are involved. To clarify the EGF-like growth factors involved in the pathology of RA, we investigated the expression levels of seven major EGF-like growth factors in RA patients compared with those in osteoarthritis (OA) patients and healthy control subjects.

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

“…These transmembrane proteins bind polypeptide ligands, mainly growth factors. Among the 58 RTK family members, epidermal growth factor receptor, plateletderived growth factor (PDGF) receptor (PDGFR), fibroblast growth factor receptor, vascular endothelial growth factor receptor, hepatocyte growth factor receptor (c-Met), and stem cell growth factor receptor (c-kit) have been shown to be expressed in rheumatoid synovial tissues (11)(12)(13)(14)(15)(16)(17)(18)(19). On the basis of their roles as growth factor receptors, several RTKs are the driving force for onset or progression of various diseases such as malignancy and arthritis and may represent key targets in therapeutic treatments.…”

Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies

“…Other investigators reported that AREG overexpression is followed by the production of several proinflammatory cytokines [20][21][22][40][41][42] in autoimmune disorder. EGFR inhibition decreased the protein expression of IL-6 by adipose tissue macrophages, reducing the proinflammatory state, 22 and TNF-a stimulates airway smooth muscle cells to express many proinflammatory mediators such as IL-6, chemokines, growth factors and adhesion molecules known to be involved in asthma.…”

“…[24][25][26] Our present hypothesis explores first, whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, [20][21][22] as second step, we discuss how TACEmediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-a-induced IL-6 and IL-8 secretion by SGEC. Finally, we evaluate the effect of adalimumab and gene silencing on AREG expression and on TNF-a-AREG-mediated proinflammatory IL-6 and IL-8 secretion.…”

“…[13][14][15] AREG is synthesized as membranebound precursor that requires metalloproteinase-mediated proteolytic cleavage to produce the soluble, mature form, 16 and is expressed from a variety of cells including human keratinocytes. [17][18][19] Various reports have shown that AREG enhances the production of several proinflammatory cytokines, [20][21][22] and, recently, it was demonstrated that TACE-mediated AREG shedding may have a critical role in the secretion of proinflammatory cytokines by human epithelial cells induced by TNF-a. 20,23 We previously demonstrated a dose-dependent increase of TACE expression in anti-Ro/SSA Abs-treated human salivary gland epithelial cells (SGEC) followed by internalization, prodomain shedding and activation of TACE protein.…”

Amphiregulin as a Novel Resistance Factor for Amrubicin in Lung Cancer Cells

“…Relative mRNA levels were calculated with the ΔΔCt method using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA as an internal control. The primers used in this study are as follows: 5'-GTGGTG CTGTCGCTCTTGATACTC-3' and 5'-TCAAATCCATCAGCACT GTGGTC-3' for AREG (13), and 5'-GCACCGTCAAGGCTG AGAAC-3' and 5'-ATGGTGGTGAAGACGCCAGT-3' for GAPDH (11). The experiments were performed in triplicate.…”