scholarly journals Synergistic activation of JNK/SAPK by interleukin-1 and platelet-derived growth factor is independent of Rac and Cdc42

1999 ◽  
Vol 338 (2) ◽  
pp. 387-392 ◽  
Author(s):  
W. DAVIS ◽  
Leonard R. STEPHENS ◽  
Phillip T. HAWKINS ◽  
Jeremy SAKLATVALA
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Rho Gtpases ◽  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Bacterial Toxins ◽  
Platelet Derived Growth Factor ◽  
Rho Proteins ◽  
Synergistic Activation ◽  
Jnk Activation

The c-Jun N-terminal kinases (JNKs) are activated strongly by inflammatory cytokines and environmental stresses, but only weakly by growth factors. Here we show that platelet-derived growth factor (PDGF) strongly potentiates activation of JNK by interleukin 1 (IL-1) in human fibroblasts and a pig aortic endothelial (PAE) cell line. This synergistic activation of JNK by IL-1 and PDGF was unaffected by bacterial toxins that inactivate Rho proteins and Ras. Since Rho proteins have been implicated in JNK activation, their possible involvement was investigated further using stably expressed, inducible N17 or V12 mutants in PAE cell lines. N17 Rac non-selectively reduced JNK activity by 30% in resting or stimulated cells (IL-1 alone, or with PDGF). N17 Cdc42 had no effect. V12 Rac weakly activated JNK and synergized with IL-1, but not with PDGF. V12 Cdc42 weakly activated JNK, but synergized with PDGF and not IL-1. Our results imply that Rho GTPases are not directly involved in mediating IL-1-induced JNK activation, or in the potentiation of this activation by PDGF.

scholarly journals Synergistic activation of JNK/SAPK by interleukin-1 and platelet-derived growth factor is independent of Rac and Cdc42

1999 ◽  
Vol 338 (2) ◽  
pp. 387 ◽  
Author(s):  
W. DAVIS ◽  
Leonard R. STEPHENS ◽  
Phillip T. HAWKINS ◽  
Jeremy SAKLATVALA
Keyword(s):  
Growth Factor ◽  
Interleukin 1 ◽  
Platelet Derived Growth Factor ◽  
Synergistic Activation

scholarly journals Stimulation of hyaluronan biosynthesis by platelet-derived growth factor-BB and transforming growth factor-β1 involves activation of protein kinase C

1995 ◽  
Vol 307 (3) ◽  
pp. 817-821 ◽  
Author(s):  
M Suzuki ◽  
T Asplund ◽  
H Yamashita ◽  
C H Heldin ◽  
P Heldin
Keyword(s):  
Protein Kinase C ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Human Fibroblasts ◽  
Transforming Growth Factor Β1 ◽  
Platelet Derived Growth Factor ◽  
Tgf Beta ◽  
Kinase C

The intracellular signal transduction pathways that mediate the stimulatory effects of platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-beta on hyaluronan biosynthesis in human fibroblasts were investigated. The stimulatory effects of both PDGF-BB and TGF-beta 1 were dependent on protein kinase C (PKC), since the PKC inhibitor calphostin C inhibited the stimulation by the growth factors. Direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) also stimulated hyaluronan production, and the combination of either PDGF-BB or TGF-beta 1 and PMA gave an increased effect. One possible mechanism for activation of PKC is via induction of phospholipase C (PLC) activity; U-17322, an inhibitor of PLC-gamma, was found to inhibit partially PDGF-BB-stimulated hyaluronan synthesis. PDGF-BB is known to activate PLC-gamma through tyrosine phosphorylation; however, a PDGF beta-receptor mutant unable to interact with and activate PLC-gamma was still able to mediate induction of hyaluronan biosynthesis, indicating that PDGF-mediated stimulation is not entirely dependent on PLC-gamma. The stimulations by PDGF-BB and TGF-beta 1 were partly dependent on protein synthesis, since parts of the effects were inhibited by cycloheximide; in contrast, the effects mediated by PMA were not. Our results indicate that PKC is involved in the transduction of the effects of growth factors on hyaluronan biosynthesis, and that the effects involve direct or indirect activation of existing hyaluronan synthetase molecules, as well as induction of new enzyme molecules.

scholarly journals The Antimicrobial Peptide Human β-Defensin-3 Accelerates Wound Healing by Promoting Angiogenesis, Cell Migration, and Proliferation Through the FGFR/JAK2/STAT3 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Miho Takahashi ◽  
Yoshie Umehara ◽  
Hainan Yue ◽  
Juan Valentin Trujillo-Paez ◽  
Ge Peng ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Growth Factors ◽  
Growth Factor ◽  
Antimicrobial Peptide ◽  
Fibroblast Growth Factor ◽  
Human Fibroblasts ◽  
Janus Kinase ◽  
Fibroblast Growth ◽  
Angiogenic Growth Factors

In addition to its antimicrobial activity, the skin-derived antimicrobial peptide human β-defensin-3 (hBD-3) promotes keratinocyte proliferation and migration to initiate the wound healing process; however, its effects on fibroblasts, which are the major cell type responsible for wound healing, remain unclear. We investigated the role of hBD-3 in cell migration, proliferation and production of angiogenic growth factors in human fibroblasts and evaluated the in vivo effect of hBD-3 on promoting wound healing and angiogenesis. Following hBD-3 treatment, the mouse wounds healed faster and showed accumulation of neutrophils and macrophages in the early phase of wound healing and reduction of these phagocytes 4 days later. hBD-3-treated wounds also displayed an increased number of fibroblasts and newly formed vessels compared to those of the control mice. Furthermore, the expression of various angiogenic growth factors was increased in the hBD-3-treated wounds. Additionally, in vitro studies demonstrated that hBD-3 enhanced the secretion of angiogenic growth factors such as fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor and induced the migration and proliferation of human fibroblasts. The hBD-3-mediated activation of fibroblasts involves the fibroblast growth factor receptor 1 (FGFR1)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways, as evidenced by the inhibitory effects of pathway-specific inhibitors. We indeed confirmed that hBD-3 enhanced the phosphorylation of FGFR1, JAK2 and STAT3. Collectively, the current study provides novel evidence that hBD-3 might be a potential candidate for the treatment of wounds through its ability to promote wound healing, angiogenesis and fibroblast activation.

Expression of recombinant platelet-derived growth factor A- and B-chain homodimers in rat-1 cells and human fibroblasts reveals differences in protein processing and autocrine effects

1988 ◽  
Vol 8 (7) ◽  
pp. 2753-2762
Author(s):  
M Bywater ◽  
F Rorsman ◽  
E Bongcam-Rudloff ◽  
G Mark ◽  
A Hammacher ◽  
...  
Keyword(s):  
Growth Factor ◽  
Human Fibroblasts ◽  
Soft Agar ◽  
Biological Properties ◽  
Platelet Derived Growth Factor ◽  
Cdna Clones ◽  
Metabolic Labeling ◽  
High Saturation ◽  
Dimeric Protein ◽  
A Chain

The autocrine effects of platelet-derived growth factor (PDGF) A- and B-chain homodimers (PDGF-AA and PDGF-BB) on rat-1 cells and human fibroblasts have been investigated by using human PDGF A- and B-chain cDNA clones expressed in a retroviral vector. Infection with replication-defective virus carrying the B-chain cDNA resulted in a phenotypical transformation resembling that induced by simian sarcoma virus. The resulting cells were focus forming in monolayer cultures, grew to high saturation densities, and formed large colonies in soft agar. The PDGF A-chain transfectants showed no transformed morphology and lacked focus-forming activity but grew to high saturation density in monolayer culture and formed small colonies in soft agar. A similar but weaker effect was obtained with an A-chain cDNA variant containing a 69-base-pair insertion in the 3' end of the protein-coding domain. A- and B-chain transfectants released PDGF receptor-competing activity into the medium, but only the medium conditioned by the B-chain transfectants possessed potent mitogenic activity on human fibroblasts. Both types of transfectants had downregulated levels of PDGF receptors; however, the B-chain transfectants were downregulated to significantly lower levels. Metabolic labeling and immunoprecipitations with PDGF antiserum showed that the PDGF B-chain protein was processed to a 24-kilodalton cell-associated and a 30-kilodalton secreted dimeric protein. The A-chain protein was rapidly secreted as a 31-kilodalton dimeric protein. The present study shows a marked difference in the autocrine effects of PDGF-AA and -BB expressed under the control of a retroviral promoter and suggests that different biological properties may be assigned to these two PDGF isoforms.

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