Response Of Dermal Fibroblasts Research Articles

Th17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts

IntroductionT helper (Th)-17 cells are increased in systemic sclerosis (SSc). We therefore assessed whether Th17 cells could modulate the inflammatory and fibrotic responses in dermal fibroblasts from healthy donors (HD) and SSc individuals.MethodsFibroblasts were obtained from 14 SSc and 8 HD skin biopsies. Th17 clones were generated from healthy peripheral blood upon enrichment of CC chemokine receptor (CCR)-4/CCR6/CD161 expressing cells. Their cytokine production was assessed by flow cytometry and multiplex beads immunoassay. Fibroblast production of monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8, matrix metalloproteinase (MMP)-1, tissue inhibitor of metalloproteinase (TIMP)-1, MMP-2 and type-I collagen was quantified by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), and changes in their transcription levels assessed by real-time PCR. Intracellular signals were dissected by western blot and the use of pharmacological inhibitors. IL-17A, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) blocking reagents were used to assess the specificity of the observed effects.ResultsIL-17A increased MCP-1, IL-8 and MMP-1 production in a dose-dependent manner while having no effect on type I collagen in HD and SSc fibroblasts both at protein and mRNA levels. Nuclear factor-kappa B (NF-κB) and p38 were preferentially involved in the induction of MCP-1 and IL-8, while MMP-1 was most dependent on c-Jun N-terminal kinase (JNK). Supernatants of activated Th17 clones largely enhanced MCP-1, IL-8 and MMP-1 while strongly inhibiting collagen production. Of note, the production of MCP-1 and IL-8 was higher, while collagen inhibition was lower in SSc compared to HD fibroblasts. The Th17 clone supernatant effects were mostly dependent on additive/synergistic activities between IL-17A, TNF and in part IFN-γ. Importantly, the inhibition of type I collagen production induced by the Th17 clone supernatants was completely abrogated by blockade of IL-17A, TNF and IFN-γ mostly in SSc fibroblasts, revealing an intrinsic resistance to inhibitory signals in SSc.ConclusionsOur findings demonstrate that in vitro Th17 cells elicit pro-inflammatory responses while restraining collagen production. Thus, the increased Th17 cell number observed in SSc may impact on the inflammatory component of the disease simultaneously potentially providing a protective role against fibrosis.

Direct comparison of the potency of human mesenchymal stem cells derived from amnion tissue, bone marrow and adipose tissue at inducing dermal fibroblast responses to cutaneous wounds

Although transplantation of human mesenchymal stem cells (MSCs) derived from amnion (hAMSCs), bone marrow (hBMSCs) and adipose tissues (hADSCs) has been shown to aid in the repair of cutaneous wounds in mouse models, little information is available regarding the relative efficacy of MSCs from different sources. In this study, we compared their therapeutic potentials by transplanting equal numbers of hAMSCs, hBMSCs or hADSCs in a mouse model of cutaneous wounds. The results suggested that an hADSC injection has the most pronounced effect on wound closure. Histological evaluation showed enhanced re-epithelialization in the hADSC group compared with the hBMSC and hAMSC groups. Although there was a slight improvement in wound healing in the hAMSC and hBMSC groups, the differences between the groups were statistically insignificant. In a trans-well coculture model, wound healing migration and transwell migration assays showed that hADSCs were superior to hAMSCs and hBMSCs at promoting human dermal fibroblast (hDF) migration. However, there was no significant difference in fibroblast proliferation between the hAMSC, hBMSC and hADSC groups, as measured by WST assay. Our results also indicated that hDFs cocultured with hADSCs for 48 h significantly upregulated their mRNA expression of the cytokine vascular endothelial growth factor, basic fibroblast growth factor, keratinocyte growth factor and transforming growth factor-β and increased the mRNA and protein levels of type I collagen. Collectively, these data suggest that hADSCs are a potential source of MSCs for therapeutic healing in cutaneous wounds in terms of efficacy, accessibility and availability.

Quantitative proteomics reveals altered expression of extracellular matrix related proteins of human primary dermal fibroblasts in response to sulfated hyaluronan and collagen applied as artificial extracellular matrix

Fibroblasts are the main matrix producing cells of the dermis and are also strongly regulated by their matrix environment which can be used to improve and guide skin wound healing processes. Here, we systematically investigated the molecular effects on primary dermal fibroblasts in response to high-sulfated hyaluronan [HA] (hsHA) by quantitative proteomics. The comparison of non- and high-sulfated HA revealed regulation of 84 of more than 1,200 quantified proteins. Based on gene enrichment we found that sulfation of HA alters extracellular matrix remodeling. The collagen degrading enzymes cathepsin K, matrix metalloproteinases-2 and -14 were found to be down-regulated on hsHA. Additionally protein expression of thrombospondin-1, decorin, collagen types I and XII were reduced, whereas the expression of trophoblast glycoprotein and collagen type VI were slightly increased. This study demonstrates that global proteomics provides a valuable tool for revealing proteins involved in molecular effects of growth substrates for further material optimization.Electronic supplementary materialThe online version of this article (doi:10.1007/s10856-012-4760-x) contains supplementary material, which is available to authorized users.

P075 Pro-inflammatory and anti-fibrotic potential of Th17 cells on human dermal fibroblast from SSc individuals

IntroductionIn systemic sclerosis (SSc), inappropriate T cell responses are thought to participate in initiating events ultimately leading to excessive extracellular matrix deposition and fibrosis.We recently demonstrated that the frequency of Th17 cells is significantly increased in SSc compared to healthy donors (HD). However, the role exerted by Th17 cells on the disease course is still poorly understood.Our purpose was to assess whether Th17 cells and IL-17A could promote inflammatory and fibrotic responses in dermal fibroblasts from HD and SSc. MethodsDermal fibroblasts were obtained from incisional biopsies of affected skin from 8 SSc and abdominoplasty surgery from 8 age- and sex-matched HD. Th17 cell clones were generated from the peripheral blood of HD upon enrichment of cells expressing CCR4/CCR6 and CD161.The cytokine production by T cell clones was assessed by FACS analysis and profiled in supernatants (SN) using multiplex beads immunoassay.Pro-inflammatory chemokines, MMP-1 and type I collagen production by IL-17A- or Th17 clone SN-treated fibroblasts was quantified by ELISA and RIA. Relative changes in steady-state gene transcription levels were assessed by real-time PCR on total mRNA from untreated vs treated-fibroblasts.IL-17 neutralizing antibody was used to confirm the specificity of the effects.Phosphorylation events induced by IL-17A were investigated by western blotting and the signaling pathways involved assessed using selective signaling protein inhibitors. ResultsIL-17A increased CCL2/MCP-1 (p<0.01), MMP-1 (p<0.01) and CXCL8/IL-8 (p<0.01) production by HD and SSc fibroblasts in a dose-dependent manner, while having no effect on type I collagen.Consistently, IL-17A increased the mRNA levels of CCL2, IL-8 and MMP-1 with no change in COL1A1 and COL1A2 mRNA. The production of CCL2/MCP-1, CXCL8/IL-8 and MMP-1 were all partially inhibited by the specific MEKK and PI3K inhibitors, indicating a wide participation of these pathways in transducing IL-17A signals.In addition, the production of CCL2/MCP-1 and CXCL8/IL-8 induced by IL-17A required NF-kB and p38 signaling, while the production of MMP-1 was dependent on JNK and AP-1 pathways.SN of activated Th17 clones strongly enhanced CCL2/MCP-1, CXCL8/IL-8 and MMP-1 production by both HD and SSc fibroblasts while inhibiting collagen synthesis.The neutralization of IL-17A in T cell clone SN reduced CCL2/MCP-1, CXCL8/IL-8 and MMP-1 and tended to enhance collagen production, thus proving the role of IL-17A in Th17 clone effects.In these SN, IL-17A had a synergistic activity with TNF as shown by simultaneous TNF/IL-17 blockade.Consistently, IL-17A/TNF co-treated fibroblasts had an enhanced production of CCL2/MCP-1, CXCL8/IL-8 and MMP-1 when compared to those subjected to each cytokine independently.Of interest, the simultaneous blockade of TNF and IL-17A in Th17 clone SN resulted in enhanced type I collagen production, specifically in SSc fibroblasts. ConclusionOur findings demonstrate that Th17 and IL-17A elicit in vitro pro-inflammatory responses and Th17 cells inhibit collagen production in human fibroblasts. Thus, the increased Th17 cell number observed in SSc may impact on the inflammatory component of the disease and may actually have a protective role against fibrosis.

A Soluble Factor from Trypanosoma cruzi Inhibits Transforming Growth Factor-ß-Induced MAP Kinase Activation and Gene Expression in Dermal Fibroblasts

The protozoan parasite Trypanosoma cruzi, which causes human Chagas' disease, exerts a variety of effects on host extracellular matrix (ECM) including proteolytic degradation of collagens and dampening of ECM gene expression. Exposure of primary human dermal fibroblasts to live infective T. cruzi trypomastigotes or their shed/secreted products results in a rapid down-regulation of the fibrogenic genes collagenIα1, fibronectin and connective tissue growth factor (CTGF/CCN2). Here we demonstrate the ability of a secreted/released T. cruzi factor to antagonize ctgf/ccn2 expression in dermal fibroblasts in response to TGF-ß, lysophosphatidic acid or serum, where agonist-induced phosphorylation of the mitogen-activated protein (MAP) kinases Erk1/2, p38 and JNK was also inhibited. Global analysis of gene expression in dermal fibroblasts identified a discrete subset of TGF-ß-inducible genes involved in cell proliferation, wound repair, and immune regulation that are inhibited by T. cruzi secreted/released factors, where the genes exhibiting the highest sensitivity to T. cruzi are known to be regulated by MAP kinase-activated transcription factors. Consistent with this observation, the Ets-family transcription factor binding site in the proximal promoter region of the ctgf/ccn2 gene (−91 bp to −84 bp) was shown to be required for T. cruzi-mediated down-regulation of ctgf/ccn2 reporter expression. The cumulative data suggest a model in which T. cruzi-derived molecules secreted/released early in the infective process dampen MAP kinase signaling and the activation of transcription factors that regulate expression of fibroblast genes involved in wound repair and tissue remodelling, including ctgf/ccn2. These findings have broader implications for local modulation of ECM synthesis/remodelling by T. cruzi during the early establishment of infection in the mammalian host and highlight the potential for pathogen-derived molecules to be exploited as tools to modulate the fibrogenic response.

Transcriptomics Evaluation of Hexavalent Chromium Toxicity in Human Dermal Fibroblasts

Significant exposure to hexavalent chromium, a metal with broad toxicity potential in humans, has been reported. In order to understand the mechanisms of dermal toxicity induced by hexavalent chromium, global gene expression profiling of human dermal fibroblasts exposed to potassium dichromate was performed. Microarray analysis of the gene expression profile in the fibroblasts treated with potassium dichromate identified significant differential expression of approximately 1,200 transcripts compared with the control cells. Functional categorization of the differentially expressed genes identified the enrichment of genes involved in several cellular processes, including apoptosis and oxidative stress, in the fibroblasts exposed to hexavalent chromium. Induction of apoptosis and oxidative stress in the dermal fibroblasts in response to their exposure to chromium was independently confirmed by additional experiments. The potassium dichromate-induced cytotoxicity, apoptosis, and oxidative stress were significantly blocked by the addition of ferrous sulfate, an agent known for its ability to reduce chromium to the insoluble and therefore impermeable trivalent form, to the cell culture medium. Taken together, our data provide insights into the potential mechanisms underlying the dermal toxicity of hexavalent chromium and provide experimental support for the proposed protective role of ferrous sulfate in hexavalent chromium-induced toxicity.

Mesenchymal stem cells induce dermal fibroblast responses to injury

Although bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds, the mechanism for this response remains to be determined. The aim of this study was to determine the effects of paracrine signaling from mesenchymal stem cells on dermal fibroblast responses to injury including proliferation, migration and expression of genes important in wound repair. Dermal fibroblasts were co-cultured with bone marrow-derived mesenchymal stem cells grown in inserts, which allowed for paracrine interactions without direct cell contact. In this co-culture model, bone marrow-derived mesenchymal stem cells regulate dermal fibroblast proliferation, migration and gene expression. When co-cultured with mesenchymal stem cells, dermal fibroblasts show increased proliferation and accelerated migration in a scratch assay. A chemotaxis assay also demonstrated that dermal fibroblasts migrate towards bone marrow-derived mesenchymal stem cells. A PCR array was used to analyze the effect of mesenchymal stem cells on dermal fibroblast gene expression. In response to mesenchymal stem cells, dermal fibroblasts up-regulate integrin alpha 7 expression and down-regulate expression of ICAM1, VCAM1 and MMP11. These observations suggest that mesenchymal stem cells may provide an important early signal for dermal fibroblast responses to cutaneous injury.

Trivalent chromium activates Rac-1 and Src and induces switch in the cell death mode in human dermal fibroblasts

In this study we examined interactions between human dermal fibroblasts and chromium acetate hydroxide originating from environmental waste sediments. We show that initially exposure of fibroblasts to Cr (III) induced membrane-dependent signaling including activation of Rac1 GTPase, Src and apoptosis signal-regulating kinase 1 (ASK-1) kinases leading to increased activities of p38 and particularly Jun N-terminal kinase (JNK) and subsequent activation of caspase-3. At later treatment intervals (48-96 h), caspase-3 activity became suppressed and markedly increased lactate dehydrogenase (LDH) release was observed. Further experiments demonstrated that LDH release occurred in the presence of increased oxidative stress, extensive DNA damage, overactivation of poly(ADP-ribose)polymerase-1 (PARP-1) and depletion of ATP. Using specific inhibitors it was demonstrated that oxidative stress along with PARP-1 activity are responsible for cell death mode switch and upon their inhibition caspase-3 activity could be restored. In conclusion, Cr (III) seems to induce a biphasic response in dermal fibroblasts, with initial apoptosis switched to necrosis via increased DNA damage and resulting PARP-1 activity.

Phospholipase C isozymes as effectors of Ras superfamily GTPases

The physiological effects of many extracellular stimuli are initiated through receptor-promoted activation of phospholipase C and inositol lipid signaling pathways. The historical view that phospholipase C-promoted signaling primarily occurs through activation of heterotrimeric G proteins or tyrosine kinases has expanded in recent years with the realization that at least three different mammalian phospholipase C isozymes are directly activated by members of the Ras superfamily of GTPases. Thus, Ras, Rap, Rac, and Rho GTPases all specifically regulate certain phospholipase C isozymes, and insight into the physiological significance of these signaling responses is beginning to accrue. High resolution three-dimensional structures of phospholipase C isozymes also are beginning to shed light on their mechanism of activation.

Endogenous bone morphogenetic proteins mediate 1α, 25‐dihydroxyvitamin D3‐induced expression of osteoblast differentiation markers in human dermal fibroblasts

Human dermal fibroblasts are generally considered to be restricted to a fibroblastic lineage. Although dermal fibroblasts do not typically express markers of osteoblastic differentiation, they have previously been shown to undergo osteoinduction when stimulated with bone morphogenetic proteins (BMPs) or vitamin D(3). However, involvement of BMP signaling in vitamin D(3)-mediated osteoinduction has not been reported. In this study, human dermal fibroblasts were cultured in chemically defined medium containing vitamin D(3), in the presence of the BMP antagonist noggin or neutralizing antibodies specific for BMP-4 or BMP-6, and characterized for markers of osteoblastic differentiation. Treatment of dermal fibroblasts with vitamin D(3) induced expression of BMP-4 (1.2 +/- 0.2, 1.7 +/- 0.2, and 1.8 +/- 0.2 relative fold increase) and BMP-6 (9.1 +/- 0.3, 23.3 +/- 2.1, and 30.4 +/- 3.0 relative fold increase) at 3, 14, and 21 days, respectively. Vitamin D(3) was also shown to induce the expression of the osteoblast-specific markers, alkaline phosphatase and osteocalcin, in a dose-dependent manner in human dermal fibroblasts. Addition of noggin, BMP-4 antibodies, and BMP-6 antibodies resulted in a downregulation of alkaline phosphatase activity (by 42%, 22%, and 20%, respectively) and secreted osteocalcin (by 20%, 31%, and 49%, respectively) after 21 days in culture. However, blocking BMP signaling did not result in complete recovery of a fibroblastic phenotype. Taken together, these results suggest that BMP signaling plays a role in the induction of an osteoblastic phenotype in human dermal fibroblasts in response to vitamin D(3) stimulation.

Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor β

Objective:Cartilage oligomeric matrix protein (COMP) accumulates in systemic sclerosis (SSc) skin and is upregulated by transforming growth factor (TGF)β. To further characterise the response to TGFβ in SSc, we investigated...

Transcriptional response of dermal fibroblasts in direct current electric fields

During the course of normal wound healing, fibroblasts at the wound edge are exposed to electric fields (EFs) ranging from 40 to 200 mV/mm. Various forms of EFs influence fibroblast migration, proliferation, and protein synthesis. Thus, EFs may contribute to fibroblast activation during wound repair. To elucidate the role of EFs during the normal progression of healing, this study compares gene expression in normal adult dermal fibroblasts exposed to a 100 mV/mm EF for 1 h to non-stimulated controls. Significantly increased expression of 162 transcripts and decreased expression of 302 transcripts was detected using microarrays, with 126 transcripts above the level of 1.4-fold increases or decreases compared to the controls. Above the level of twofold, only 11 genes were significantly increased or decreased compared to controls. Many of these significantly regulated genes are associated with wound repair through the processes of matrix production, cellular signaling, and growth. Activity within specific cellular signaling pathways is noted, including TGF-beta, G-proteins, and inhibition of apoptosis. In addition, RT-PCR analysis of the expression of KLF6, FN1, RGS2, and JMJD1C over continued stimulation and at different field strengths suggests that there are specific windows of field characteristics for maximum induction of these genes. EFs thus appear to have an important role in controlling fibroblast activity in the process of wound healing.

Differential regulation of free‐floating collagen gel contraction by human fetal and adult dermal fibroblasts in response to prostaglandin E2 mediated by an EP2/cAMP‐dependent mechanism

In contrast to fetal wound healing, dermal adult wound healing results in imperfect repair and scar formation. Fibroblasts are responsible for the contraction and remodeling of the wound matrix, which is influenced by inflammatory mediators including prostaglandin E2 (PGE2). This study addresses the mechanism by which PGE2 regulates contraction of collagen gels by human fetal and adult dermal fibroblasts. We hypothesized that the intrinsic phenotypic properties of the two types of fibroblasts and their responses to PGE2 alter their contraction properties and contribute to different wound healing outcomes. Contraction was evaluated using free-floating fibroblast-populated collagen gels that contract by migratory forces. PGE2 was found to differentially inhibit collagen gel contraction by fetal and adult fibroblasts. This effect was mimicked by a specific PGE2 receptor agonist as well as by two pharmacological agents, indicating a cyclic adenosine monophosphate-dependent signaling pathway mediated through the EP2 receptor. Our results indicate that fetal fibroblast contraction is maintained by a more stable actin cytoskeleton. Therefore, the migratory phenotype may be sufficient for physical remodeling of the wound matrix leading to regenerative repair. Maintenance of this phenotype in the later stages of wound healing could potentially be achieved by targeting cyclic adenosine monophosphate via the EP2 receptor.

Keratinocyte conditioned medium abrogates the modulatory effects of IGF‐1 and TGF‐β1 on collagenase expression in dermal fibroblasts

Overexpression of wound healing-promoting factors such as transforming growth factor-1 (TGF-beta1) and insulin-like growth factor-1 (IGF-1) during the healing process has been implicated in the development of dermal fibrosis in patients following thermal injury, surgical incision, and deep trauma. However, the mechanism through which the expression of these two fibrogenic factors is slowed down and/or abrogated in the late stages of the healing process is not known. Here, we hypothesize that keratinocyte-releasable factors counteract the fibrogenic role of both IGF-1 and TGF-beta1 in fibroblasts. To test this hypothesis, the levels of collagenase (MMP-1), as an index for extracellular matrix degradation, in dermal fibroblasts in response to either keratinocyte-conditioned medium (KCM) or our recently identified keratinocyte-releasable stratifin in the presence and absence of either IGF-1, TGF-beta1, or both were evaluated. The results of Northern analysis showed a significant increase in collagenase mRNA expression in cells treated with KCM in the presence of both IGF-1 and TGF-beta1. The effect was, at least in part, due to keratinocyte-derived stratifin that was present in KCM. This was ascertained as the levels of MMP-1 mRNA were markedly reduced when cells were treated with stratifin-immuno-depleted KCM. The results of Western blot analysis showed an increase in the level of MMP-1 protein in stratifin-treated fibroblasts and this was consistent with the level of MMP-1 mRNA expression detected by Northern analysis. However, in contrast to KCM, whose efficacy on MMP-1 expression was modestly reduced by either IGF-1 and TGF-beta1, or a combination of both, these factors abrogated the MMP-1 stimulatory effect of stratifin in fibroblasts. In summary, the results of this study revealed that both stratifin and KCM stimulate the expression of MMP-1-in fibroblasts and this effect can be abrogated by either IGF-1, TGF-beta1, or a combination of both.

Anti‐inflammatory effects of CoQ10 and colorless carotenoids

CoQ10 (ubiquinone, coenzyme Q10) and carotenoids are popular antioxidants used in many skin care products to protect the skin from free radical damage. To evaluate the effects of CoQ10 and colorless carotenoids on the production of inflammatory mediators in human dermal fibroblasts treated with UV radiation (UVR) and to investigate the possible synergistic effects of these two antioxidants. Normal human dermal fibroblast cell cultures were exposed to either 50 mJ of UVR or to IL-1 and then incubated with various concentrations of either CoQ10, the colorless carotenoids, phytoene and phytofluene, or to combinations of these antioxidants. After 24 h in culture, cells and spent medium were harvested and assayed by enzyme-linked immunosorbent assay for prostaglandin E2 (PGE-2), interleukin 6 (IL-6), and matrix metalloproteinase 1 (MMP-1). In addition, the ability of the carotenoids to protect CoQ10 from oxidation by the reactive oxygen species (ROS), hyperchlorite, was also determined. Human fibroblasts respond to UVR or to IL-1 by increasing the production of various inflammatory mediators including PGE-2, IL-1, and IL-6 and proteases such as collagenase (MMP-1). Treatment of fibroblasts with 10 microm of CoQ10 suppressed the UVR- or IL-1-induced increase in PGE-2, IL-6, and MMP-1. The combination of carotenoids and CoQ10 produced an enhanced inhibition of these three inflammatory mediators. Furthermore, the colorless carotenoids, phytoene and phytofluene, protected CoQ10 from degradation by the ROS, hypochlorite. CoQ10 is able to suppress the UVR- or IL-1-induced inflammatory response in dermal fibroblasts. Furthermore, this compound can block the UVR induction of the matrix-eroding enzyme, MMP-1. Finally, the combination of carotenoids plus CoQ10 results in enhanced suppression of inflammation. The results suggest that the combination of carotenoids and CoQ10 in topical skin care products may provide enhanced protection from inflammation and premature aging caused by sun exposure.

Increased Expression of Integrin αvβ5 Induces the Myofibroblastic Differentiation of Dermal Fibroblasts

The biological effect of cytokines is mainly determined by the cytokine-receptor interaction, which is modulated by the concentration and the activity of cytokines and/or their receptors. Because alphav-containing integrins can bind to and/or activate latent TGF-beta, these integrins have been thought to be involved in the pathogenesis of fibrotic disorders. Our recent observations that alphavbeta5 is up-regulated in scleroderma fibroblasts and that the transient overexpression of alphavbeta5 increases the human alpha2(I) collagen gene expression in normal fibroblasts suggest the involvement of alphavbeta5 in the self-activation system in scleroderma fibroblasts. In this study, we established stable transfectants with alphavbeta5 using normal dermal fibroblasts and demonstrated that such cells differentiated into myofibroblasts by the stimulation of autocrine TGF-beta. This observation is explained by 1) alphavbeta5 recruiting latent TGF-beta1 on the cell surface, 2) endogenous active TGF-beta localizing on the cell surface, and 3) alphavbeta5 interacting with TGF-beta receptors. Furthermore, blockade of alphavbeta5 reversed the myofibroblastic phenotype in scleroderma fibroblasts. These data identify a novel mechanism for the establishment of autocrine TGF-beta signaling in dermal fibroblasts by the up-regulation of alphavbeta5 and suggest the possibility of regulating fibrotic disorders, especially scleroderma, by targeting this integrin.

PI3K signaling and miRNA expression during the response of quiescent human fibroblasts to distinct proliferative stimuli

Global transcriptional profiling of human fibroblasts from two different tissue sources reveals distinct as well as conserved responses to different growth stimuli.

Skinomics

Skinomics

Increased Expression of Growth Factor Receptors in Dermal Fibroblasts in Response to Hyperbaric Oxygen (HBO) Is Nitric Oxide (NO)-dependent

Increased Expression of Growth Factor Receptors in Dermal Fibroblasts in Response to Hyperbaric Oxygen (HBO) Is Nitric Oxide (NO)-dependent

Interleukin 6 Indirectly Induces Keratinocyte Migration

IL-6-deficient transgenic mice (IL-6 KO) display significantly delayed cutaneous wound healing. To further elucidate the role of IL-6 in skin wound healing, epidermal keratinocyte and dermal fibroblast cells were isolated from neonatal IL-6 KO mice and treated with rmIL-6. It was found that rmIL-6 alone did not significantly modulate the proliferation or migration of cultured IL-6 KO keratinocytes. rmIL-6, however, significantly induced the migration of IL-6 KO keratinocytes (up to 5-fold) when co-cultured with dermal fibroblasts. Culture supernatants from IL-6-treated fibroblasts were also found to induce the migration of keratinocytes to a similar degree. Genomics analysis of treated fibroblasts indicated that rmIL-6 does not induce any known soluble keratinocyte migratory factors. rmIL-6 treatment of fibroblast, however, induced a rapid and sustained phosphorylation of STAT3 protein. These data indicate that IL-6 could influence wound healing by inducing keratinocyte migration through the production of a soluble fibroblast-derived factor, and its activity may be associated with STAT3 activation.