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PubMed2002

Distinct pathways of lipopolysaccharide priming of human neutrophil respiratory burst: role of lipid mediator synthesis and sensitivity to interleukin-10.

OBJECTIVE: Exposure of neutrophils to low doses of bacterial lipopolysaccharides enhances their readiness to respond with inflammatory mediator generation including oxygen radical formation to a subsequently applied inflammatory stimulus ("priming"). In the present study, we investigated the role of lipid mediator synthesis and the impact of the anti-inflammatory cytokine interleukin-10 on the lipopolysaccharide-dependent priming of human neutrophils in response to N-formyl-methionyl-leucyl-phenylalanine. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university hospital. SUBJECTS: Isolated neutrophils from healthy volunteers. INTERVENTIONS: Incubation of isolated neutrophils with endotoxin. MEASUREMENTS AND MAIN RESULTS: Evidence for two distinct priming mechanisms was obtained. The first was strictly serum component dependent, proceeded via CD14, and was not inhibited by even high concentrations of interleukin-10. The second priming mechanism was serum component independent but nevertheless proceeded via CD14. It was linked with neutrophil synthesis of the platelet activating factor and resulted in the appearance of leukotrienes, in particular leukotriene B4, as far as exogenous arachidonic acid was provided. The employment of a platelet-activating factor receptor antagonist (WEB 2086) blocked leukotriene synthesis, and both WEB 2086 and a 5-lipoxygenase inhibitor (MK-886) suppressed the respiratory burst linked with this second priming pathway. This sequence of priming events was inhibited by interleukin-10, when this cytokine was coadministered with the priming agent lipopolysaccharide, whereas late interleukin-10 admixture was ineffective. CONCLUSIONS: We conclude that two mechanisms of lipopolysaccharide priming of human neutrophil respiratory burst can be differentiated. One displays serum component dependence, is independent of neutrophil lipid mediator generation, and is not affected by interleukin-10. The other is serum independent although being operated via CD14, employs autocrine loops of platelet-activating factor and leukotriene B4 synthesis, and is sensitive to the inhibitory capacity of interleukin-10. These features may be relevant when the goal is to pharmacologically modify neutrophil functions in septic events.

Arachidonic Acid↗
PubMed1999

Effect of omega-conotoxin GVIA and omega-agatoxin IVA on the capsaicin-sensitive calcitonin gene-related peptide release and autoregulatory vasodilation in rat pial arteries.

This study assesses the effect of neuronal voltage-sensitive Ca2+ channel blockers, omega-conotoxin GVIA (CTX), and omega-agatoxin IVA (AgTX) on the vasodilation and release of calcitonin gene-related peptide (CGRP), both of which were induced by either application of capsaicin or acute stepwise hypotension. Changes in pial arterial diameter were determined directly through a closed cranial window. The vasodilation of pial artery induced by either CGRP (0.1 micromol/L) or capsaicin (0.3 micromol/L) was significantly inhibited by CGRP(8-37) (0.1 micromol/L) (P < 0.05 and P < 0.05, respectively). The autoregulatory vasodilation to acute stepwise hypotension was severely attenuated by pretreatment with either CTX or AgTX. When the hypotension was kept for 2, 4, and 10 minutes, the releasable CGRP-like immunoreactivity (CGRP-LI) level (vehicle, 13.4+/-1.5 fmol/mm2/30 min) by 10 micromol/L capsaicin from the isolated pial arteries was significantly reduced in the 4- and 10-minute hypotension groups (11.3+/-1.2 fmol/mm2/30 min, P < 0.05, and 11.1+/-1.5 fmol/mm2/30 min, P < 0.05, respectively), but not in 2-min group. Moreover, the CGRP-LI level released by 10 micromol/L capsaicin (13.7+/-0.9 fmol/mm2/30 min) also was significantly depressed by pretreatment with 1 micromol/L CTX to 10.4+/-1.0 fmol/mm2/30 min (P < 0.01) and with 0.1 micromol/L AgTX to 8.7(1.7 fmol/mm2/30 min (P < 0.001), as well as by pretreatment with 10 micro-mol/L capsaicin (6.0+/-1.6 fmol/ mm2/30 min, P < 0.001). These results suggest that the neuronal N- and P-type voltage-sensitive Ca2+ channels are implicated in the release of CGRP from capsaicin-sensitive perivascular sensory nerves in response to acute hypotension, and that the released CGRP may contribute to the autoregulatory vasodilation in the cerebral microcirculation.

Animals↗
PubMed2004

Substance P enhances expression of lipopolysaccharide-induced inflammatory factors in dental pulp cells.

To examine how substance P (SP) is related with dental pulp inflammation, we examined the effects of SP on expression of genes for inflammatory factors in human dental pulp cell cultures. Using reverse transcriptase-polymerase chain reaction, we found that Prevotella intermedia lipopolysaccharide (LPS) induced expression of SP and SP-receptor mRNAs, and that somatostatin inhibited the LPS-induced expression of SP mRNA. We also found that SP enhanced LPS-induced stimulation of NF-kappaB binding activity. In addition, SP induced expression of cyclooxygenase-2 and interleukin-10 receptor mRNAs. In contrast, SP inhibited expression of interferon-gamma receptor mRNA. These results suggest that SP may play a regulatory role in the immunological response of dental pulp tissue to pathogenic bacteria.

Autocrine Communication↗
PubMed2002

Dura mater biology: autocrine and paracrine effects of fibroblast growth factor 2.

The dura mater, the outermost layer of the meninges, is thought to be essential for calvarial morphogenesis, postnatal suture fusion, and osseous repair of calvarial defects. Despite numerous studies illustrating the fundamental role of the dura mater, there is little information about the autocrine and paracrine mechanisms regulating dural cell biology during calvarial ossification. Previous work conducted in the authors' laboratory demonstrated that non-suture-associated dural cells from 6-day-old rat pups expressed high levels of fibroblast growth factor 2 (FGF-2), whereas dural cells from 60-day-old adult rats expressed very little FGF-2. Because young mammals can successfully heal large calvarial defects, the authors sought to investigate the autocrine and/or paracrine effects of FGF-2 on the proliferation, gene expression, and alkaline phosphatase production of dural cells. Cultures of non-suture-associated dural cells were established from 6-day-old Sprague-Dawley rat pups and then stimulated with recombinant human FGF-2 (rhFGF-2; 10 ng/ml). Dural cells stimulated with rhFGF-2 proliferated significantly faster than untreated dural cells at 24 hours (2.1 x 10(5) +/- 3.2 x 10(4) versus 1.1 x 10(5) +/- 1.8 x 10(4), p < or = 0.001) and 48 hours (2.3 x 10(5) +/- 4.2 x 10(4) versus 1.2 x 10(5) +/- 1.3 x 10(4), p < or = 0.001). Moreover, dural cells stimulated with rhFGF-2 expressed 7-fold more proliferating cell nuclear antigen than did control cultures. Treatment with rhFGF-2 increased dural cell expression of genes important for skeletal repair: FGF-2 (7-fold), transforming growth factor beta 1 (3-fold), transforming growth factor beta 3 (4-fold), and type I collagen (4-fold). Furthermore, rhFGF-2 increased dural cell expression of osteopontin (2-fold), a "late" marker of osteoblastic differentiation. Interestingly, dural cell alkaline phosphatase activity, an "earlier" marker of osteoblast differentiation, was significantly decreased by treatment with rhFGF-2 compared with control cultures at 24 hours (0.005 +/- 0.001 versus 0.01 +/- 0.003, p < or = 0.01) and 48 hours (0.004 +/- 0.0009 versus 0.01 +/- 0.0009). Together these data provide insight into the autocrine and paracrine effects of FGF-2 on the biology of the dura mater.

Alkaline Phosphatase↗
PubMed2002

Cimetidine and a tamoxifen derivate reduce tumour formation in SCID mice xenotransplanted with a human melanoma cell line.

Histamine is produced by many cells expressing histidine decarboxylase (HDC), the enzyme responsible for the synthesis of histamine. Since melanoma cells and tissue contain relatively large amounts of histamine, the functional significance of histamine was examined using specific antihistamines in vitro and in vivo in the human melanoma cell line HT168 and severe combined immunodeficiency (SCID) mice. It was shown that the H2 receptor antagonist cimetidine when combined with N, N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl (DPPE), a tamoxifen derivate, inhibits the proliferation of HT168 cells. Furthermore, it is suggested that there is a factor(s) that interferes with the exponential growth of HT168 cells xenografted to immunodeficient mice, and cimetidine and DPPE together significantly influence this factor(s). This combination of antihistamines also increases the survival of human melanoma-grafted mice. These changes are accompanied by enhanced infiltration of interferon-gamma- producing mouse macrophages into the tumour tissue. These findings suggest that two different mechanisms are probably acting concordantly: direct inhibition of tumour cell proliferation by the H2 receptor antagonists, and activation of the local immune response characterized by interferon-gamma production. These findings may help to elucidate the possibility of a rationally designed antihistamine strategy in melanoma therapy.

Animals↗
PubMed2004

The role of VEGF-A in glomerular development and function.

PURPOSE OF REVIEW: Vascular endothelial growth factor is a major regulator of blood vessel biology and is highly expressed in presumptive and mature podocytes within the glomerulus. It has long been recognized that dysregulation of this factor occurs in a number of glomerular diseases; however, definitive proof that it plays a pathogenic or developmental role in glomerular biology has remained elusive. This review will summarize some of the recent advances in our understanding of the role(s) of VEGF in these processes. RECENT FINDINGS: Gene targeting in the mouse has shown that tight regulation of vascular endothelial growth factor is required for development and maintenance of the glomerular filtration barrier. Podocyte-specific deletion of both alleles leads to congenital nephropathy and perinatal lethality. The glomeruli of mice that lack the 164 and 184 isoforms but express the 120 isoform, are smaller and have fewer capillary loops, whereas mice with podocyte-specific haploinsufficiency for all isoforms develop glomerular endotheliosis, the renal lesion seen in preeclampsia. Elevated levels of the soluble vascular endothelial growth factor receptor 1, which binds and inhibits circulating forms of VEGF were identified in patients with preeclampsia; rats injected with this soluble receptor develop hypertension, endotheliosis and proteinuria, similar to the lesion seen in podocyte-specific haploinsufficient VEGF mice. Conversely, podocyte-specific overexpression of the 164 isoform leads to collapsing glomerulopathy, the classic lesion seen in HIV-associated nephropathy. SUMMARY: These results demonstrate that vascular endothelial growth factor plays a critical role in glomerular development and function, and provides the foundation to develop novel diagnostic or therapeutic tools for patients with glomerular disease.

Animals↗
PubMed2004

Expression of neuregulin and activation of erbB receptors in vestibular schwannomas: possible autocrine loop stimulation.

HYPOTHESIS: We sought to determine whether vestibular schwannomas are capable of producing and responding to the glial growth factor neuregulin. BACKGROUND: Neuregulin is a neuronally derived trophic factor that interacts with erbB2 and erbB3 receptors on Schwann cells and is required for normal Schwann cell proliferation, survival, and development. Vestibular schwannomas grow several millimeters or even centimeters away from adjacent axons, suggesting that vestibular schwannomas do not depend critically on axons for their proliferation or survival. This raises the possibility that vestibular schwannomas themselves produce and respond to trophic factors in an autocrine fashion. METHODS: Pathologic specimens from eight patients undergoing microsurgical removal of vestibular schwannomas and one patient undergoing vestibular nerve section were immunostained with anti-neuregulin, anti-erbB2, anti-erbB3, and anti-phosphorylated-erbB2 antibodies. Three patients had received previous gamma knife radiation therapy and two patients had neurofibromatosis Type 2. RESULTS: The Scarpa ganglion neurons express neuregulin, and normal vestibular Schwann cells express erbB2 and erbB3. Vestibular schwannomas from all eight patients demonstrated neuregulin, erbB2, and erbB3 immunoreactivity. In addition, all vestibular schwannomas demonstrated immunoreactivity to anti-phosphorylated-erbB2 antibody that only recognizes erbB2 when it is phosphorylated, or activated. CONCLUSION: These results demonstrate that vestibular schwannomas express neuregulin and its receptors, erbB2 and erbB3. Because erbB2 exists in an activated state, as evidenced by phosphorylated-erbB2 immunoreactivity, it likely responds to the locally produced neuregulin. This suggests the possibility that vestibular schwannomas produce and respond to neuregulin in an autocrine fashion.

Adolescent↗
PubMed2002

Prevention of diabetic nephropathy in rats by prostaglandin E receptor EP1-selective antagonist.

Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-beta (TGF-beta) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-beta and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.

Animals↗
PubMed2003

Production of the novel mesangial autocrine growth factors GDNF and IL-10 is regulated by the immunomodulator AS101.

Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of various glomerular diseases. This study shows that glial cell line-derived neurotrophic factor (GDNF) and IL-10 are mesangial autocrine growth factors that play a pivotal role in rat MC proliferation in vitro. Downstream targets of GDNF signaling and their role in MC hyperplasia are identified. The phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target NF-kappaB were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27(kip1) expression, resulting in the increased formation of cyclin D1/cdk4 and cyclin E/cdk2 complexes, followed by hyperphosphorylation of retinoblastoma, a key event for G1 to S phase progression. IL-10 appears to be a more potent MC growth factor that negatively regulates GDNF expression. Indeed, its inhibition by the nontoxic tellurium anti-IL-10 compound, ammonium trichloro(dioxoethylene-o,o') tellurate (AS101), extensively decreased MC clonogenicity despite GDNF upregulation. Identification of the mesangial GDNF and IL-10 pathways as critical mediators of mesangial cell proliferation may provide another target for therapeutic intervention in certain glomerular diseases. In vivo animal studies using AS101, currently undergoing phase II clinical trials on cancer patients, are warranted to determine its potential in the management of glomerular diseases associated with mesangial cell proliferation.

Adjuvants, Immunologic↗
PubMed2005

An autocrine or paracrine Fas-mediated counterattack: a potential mechanism for apoptosis of notochordal cells in intact rat nucleus pulposus.

STUDY DESIGN: Immunohistochemistry and in situ nick end-labeling (TUNEL) were performed in rat lumbar intervertebral discs. OBJECTIVES: To demonstrate the mechanism of notochordal cell death in the nucleus pulposus (NP). SUMMARY OF BACKGROUND DATA: With age, notochordal cells gradually disappear in the NP. We hypothesized that this phenomenon might be related to Fas-mediated apoptosis. MATERIALS AND METHODS: Expressions of Fas; Fas ligand (FasL); caspase 3, 8, 9, 10; Ki-67 protein; and TUNEL were examined in 4-week-, 6-month- and 12-month-old rat NPs. Apoptosis (TUNEL-positive) and proliferation potential (Ki-67-positive) indexes of notochordal cells were calculated and compared among age groups. RESULTS: Notochordal cells constitutively expressed both Fas and FasL. Among their downstream initiator (caspase 8, 9, and 10) and executioner (caspase 3) caspases tested, caspase 9 and 3 were expressed. Proliferation potential of the notochordal cells was the highest at 4 weeks (1.96 +/- 1.3%) and decreased to a significantly lower level at 6 (0.81 +/- 0.68%) and 12 months (0.8 +/- 0.37%; P = 0.03 and 0.01, respectively). In contrast, apoptosis of the notochordal cells was the lowest at 4 weeks (3.52 +/- 1.07%) and increased to a significantly higher level at 6 (19.38 +/- 10.99%) and 12 months (21.51 +/- 16.99%; P < 0.001 in both comparisons). CONCLUSIONS: Fas-mediated mitochondrial caspase 9 pathway is constitutively present in the rat notochordal cells. The constitutive expression of Fas, FasL and its downstream caspases, as well as the homogeneity ofnotochordal cell population suggests an autocrine or paracrine Fas-mediated counterattack to be a potential mechanism for apoptosis of rat notochordal cells. A regulated negative balance of notochordal cell proliferation against apoptosis is likely to involve the disappearance of notochordal cells in the rat NP. This information on the mechanism for apoptosis of notochordal cells could be important in the investigation of intervertebral disc development as well as aging and perhaps degeneration.

Aging↗
PubMed2003

Androgen dependent regulation of bacillus Calmette-Guerin induced interleukin-6 expression in human transitional carcinoma cell lines.

PURPOSE: Autocrine expression of interleukin (IL)-6 by transitional cell carcinoma (TCC) in response to bacillus Calmette-Guerin (BCG) may have an important role in promoting BCG adherence to TCC and consequently in BCG treatment efficacy. IL-6 expression in response to BCG requires nuclear factor (NF)-kappaB mediated signal transduction. We evaluated the influence of androgens on BCG induced, NF-kappaB mediated IL-6 expression. MATERIALS AND METHODS: Reverse transcriptase-polymerase chain reaction was used to confirm androgen receptor expression in the human TCC lines 253J and T24. A reporter construct containing an androgen response element was used to establish the integrity of androgen mediated signal transduction. Subsequently the dose dependent effect of dihydrotestosterone (DHT) on BCG induced IL-6 expression and NF-kappaB signaling was evaluated. Two pharmacological androgen receptor blockers were used to determine if receptor blockade inhibited the effect of DHT on activation of the androgen response element, NF-kappaB signaling and BCG induced IL-6 expression. RESULTS: The 2 human TCC lines expressed androgen receptor and demonstrated intact androgen stimulated signaling pathways. DHT suppressed BCG induced, NF-kappaB mediated signaling and IL-6 expression in a dose dependent manner. DHT decreased mRNA levels of IL-6, expression of the full-length IL-6 promoter construct and expression of an NF-kappaB specific reporter construct in response to BCG relative to controls. Competitive pharmacological blockade of androgen receptor inhibited the effect of DHT on BCG induced signaling in dose dependent fashion. CONCLUSIONS: DHT down-regulates NF-kappaB mediated IL-6 expression by human TCC lines in response to BCG. This effect depends on a functional androgen receptor signaling pathway and it can be blocked by the inhibition of androgen/androgen receptor binding.

Androgen Antagonists↗
PubMed2004

Autocrine over expression of fibronectin by human transitional carcinoma cells impairs bacillus Calmette-Guerin adherence and signaling.

PURPOSE: Bacillus Calmette-Guerin (BCG) binds to the tumor cell as a result of mycobacterial receptors for fibronectin (FN). Cell surface bound FN serves as a bridge through which BCG attaches to the tumor cell. Despite the importance of FN studies have demonstrated an idiosyncratic decrease in BCG adherence in response to exogenous FN. We evaluated the effect of exogenous and autocrine FN on the ability of BCG to adhere to the tumor cell surface and initiate cellular signaling. MATERIALS AND METHODS: BCG adherence to parental 253J and FN over expressing 253JTGFbeta1-8 cells as well as to the intrinsic FN expressing cell line 647V was quantified using green fluorescent protein-BCG. Experiments were performed to assess the effect of FN on BCG initiated signal transduction through nuclear factor kappaB and AP1. Finally, the integrity of the BCG activated signaling pathway in transforming growth factor-beta1/FN over expressors was assessed using antibody mediated cross-linking of the FN receptor. RESULTS: BCG adherence was decreased in cell lines with high autocrine expression of FN. Exogenous FN prevented BCG induced transactivation of nuclear factor kappaB and AP1 reporter constructs. No BCG stimulated signaling to these reporters could be detected in FN over expressing 253J cells. NonFN dependent alpha5beta1 cross-linking initiated signal transduction in FN over expressing cells. CONCLUSIONS: We propose that by saturating cellular and BCG receptors excess FN expression decreases the ability of cellular or mycobacterial bound FN to bind vacant receptors on BCG or on the cell. Excess FN inhibits BCG adherence and BCG initiated signal transduction.

Autocrine Communication↗
PubMed2004

The role of the vitamin K-dependent growth factor Gas6 in glomerular pathophysiology.

PURPOSE OF REVIEW: The product of growth arrest-specific gene 6 (gas6) is a unique vitamin K-dependent growth-potentiating factor for vascular smooth muscle cells, and anticoagulant warfarin inhibits the activation process of the protein. It has been reported that Gas6 is also a mitogen for mesangial cells, and that warfarin inhibits mesangial cell proliferation by blocking the activation of Gas6. A recent series of studies has revealed the in-vivo roles of Gas6 and its receptor Axl in the progression of various kidney diseases. This review summarizes these studies and discusses the possible interventions targeting the Gas6/Axl pathway to prevent the progression of kidney diseases. RECENT FINDINGS: The expression of Gas6 and Axl is upregulated in an acute model of glomerulonephritis in rats, and the interference of the Gas6/Axl pathway by warfarin or the extracellular domain of Axl inhibits the progression of diseases. Induction of chronic glomerulonephritis in Gas6 mice results in less mortality, proteinuria, and histological changes of kidneys compared to wild-type mice. Administration of recombinant Gas6 reverses these phenotypes. Expression of Gas6 is also upregulated in streptozotocin-induced diabetic nephropathy, and administration of low-dose warfarin decreases albuminuria and hypertrophy of glomeruli. Possible roles of Gas6 are also reported in renal allograft dysfunction of rats and humans. SUMMARY: The importance of the Gas6/Axl pathway has been implicated in many types of kidney disease. Further investigations on the role of the Gas6/Axl pathway in human kidney diseases and the development of specific antagonists targeting the pathway are warranted.

Animals↗
PubMed2006

Molecular biology of the small intestine.

PURPOSE OF REVIEW: A concise report of published research is presented here that has provided new insights into the molecular and cell biology of the small intestine. RECENT FINDINGS: The precise control of cell renewal lineage commitment, differentiation and apoptosis along the crypt-villus axis are regulated by paracrine and autocrine signaling pathways that include Wnt, Hedgehog and Notch ligands. The downstream signaling pathways and transcriptional control of gene expression are being elucidated. Conditional loss of functional c-myc in the intestinal mucosa may have no effect on the normal homeostasis of this tissue. Manipulation of CUGBP2 expression may modulate the response of normal intestine to radiation therapy. SUMMARY: The cellular interactions at various levels in the small intestine are being understood and would provide a framework for interventional translational research in coming years.

Animals↗
PubMed2002

Requirement of fibroblast growth factor 10 in development of white adipose tissue.

Fibroblast growth factors (FGFs) are important intercellular signaling molecules in developmental processes. Here, we show that FGF10 is secreted by cultured preadipocytes and that prevention of FGF10 signaling inhibits the expression of C/EBPbeta and the subsequent differentiation of these cells. An active form of C/EBPbeta rescued differentiation of the cells in which FGF10 signaling was blocked. Development of white adipose tissue and the expression of C/EBPbeta in this tissue of FGF10 knockout mice were markedly reduced, and the ability of embryonic fibroblasts derived from FGF10 knockout mice to differentiate into adipocytes was impaired. Therefore, FGF10 plays an important role in adipogenesis, at least partly by contributing to the expression of C/EBPbeta through an autocrine/paracrine mechanism.

Adipocytes↗
PubMed2004

Signal propagation and failure in discrete autocrine relays.

A mechanistic model of discrete one-dimensional arrays of autocrine cells interacting via diffusible signals is investigated. Under physiologically relevant assumptions, the model is reduced to a system of ordinary differential equations for the intracellular variables, with a particular, biophysically derived type of long-range coupling between cells. Exact discrete traveling wave and static kink solutions are obtained in the model with sharp threshold nonlinearity. It is argued that the considered mechanism may be used extensively for transmission of information in tissues during homeostasis and development.

Autocrine Communication↗
PubMed2004

Autocrine catecholamine biosynthesis and the beta-adrenoceptor signal promote pigmentation in human epidermal melanocytes.

Earlier it has been shown that human proliferating/undifferentiated basal keratinocytes hold the full capacity for autocrine catecholamine synthesis/degradation and express beta2-adrenoceptors (beta2-AR). In this report, we show that human melanocytes also express all of the mRNA and enzymes for autocrine synthesis of norepinephrine but fail to produce epinephrine. So far, it was established that human melanocytes express alpha1-AR which are induced by norepinephrine yielding the inosine triphosphate diacylglycerol signal. The presence of catecholamine synthesis and the beta2-AR signal escaped definition at that time. Using RT-PCR, immunofluorescence and radioligand binding with the beta2-AR antagonist (-)-[3H]CGP 12177, we show here that human melanocytes express functional beta2-AR (4230 receptors per cell) with a Bmax at 129.3 and a KD of 3.19 nM but lack beta1-AR expression. beta2-AR stimulation with epinephrine 10(-6) M and salbutamol 10(-6)-10(-5) M yielded a strong cyclic adenosine monophospate (cAMP) response in association with upregulated melanin production. Taken together these results indicate that the biosynthesis and release of epinephrine (10(-6) M) by surrounding keratinocytes can provide the cAMP response leading to melanogenesis in melanocytes via the beta2-AR signal. Moreover, the discovery of this catecholaminergic cAMP response in melanocytes adds a new source for this important second messenger in melanogenesis.

Autocrine Communication↗
PubMed2004

Heat shock-induced matrix metalloproteinase (MMP)-1 and MMP-3 are mediated through ERK and JNK activation and via an autocrine interleukin-6 loop.

Although many studies have been performed to elucidate the molecular consequences of ultraviolet irradiation, little is known about the effect of infrared radiation on skin aging. In addition to photons, heat is likely to be generated as a consequence of infrared irradiation, and heat shock is widely considered to be an environmental stress. Here we investigated the effect of heat shock on the expressions of matrix metalloproteinase (MMP)-1, MMP-2, and MMP-3 in cultured human skin fibroblasts. Heat shock induced the expression of MMP-1 and MMP-3, but not MMP-2, at the mRNA and protein levels in a temperature-dependent manner, and caused the rapid activation of three distinct mitogen-activated protein kinases (MAPK), extracelluar signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. The heat shock-induced MMP-1 and MMP-3 expression was suppressed by the inhibition of ERK and JNK but not by p38 MAPK inhibition. Furthermore, heat shock increased the synthesis and release of interleukin-6 (IL-6) into culture media. The specific inhibition of IL-6 using a monoclonal antibody against IL-6 greatly reduced the expression of MMP-1 and MMP-3 induced by heat shock. Taken together, our results suggest that ERK and JNK play an important role in the induction of MMP-1 and MMP-3 by heat shock and that the heat shock-induced expression of MMP-1 and MMP-3 is mediated via an IL-6-dependent autocrine mechanism.

Antibodies↗