Publications (8) View all
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Article: Dichotomy of CCL21 and CXCR3 in nerve injury-evoked and autoimmunity-evoked hyperalgesia.
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ABSTRACT: The chemokine CCL21 is released from injured neurons and acts as a ligand of the chemokine receptor, CXCR3, which likely contributes to pro-inflammatory adaptations and secondary neuronal damage. CCL21-CXCR3 signalling may therefore impact on the development of neuropathic pain. By using the respective knockout mice we show that deficiency of CCL19/21 in plt/plt mice attenuates nerve injury evoked pain but not the hyperalgesia evoked by autoimmune encephalomyelitis (EAE). Oppositely, CXCR3-deficiency had no protective effect after traumatic nerve injury but reduced EAE-evoked hyperalgesia and was associated with reduced clinical EAE scores, a reduction of the pro-inflammatory cell infiltration and reduced upregulation of interferon gamma and interleukin-17 in the spinal cord. In contrast, microglia activation in the spinal cord after traumatic sciatic nerve injury was neither attenuated in CXCR3(-/-) nor plt/plt mice, nor in double knockouts. However, the severity of EAE, but not the hyperalgesia, was also reduced in plt/plt mice, which was associated with reduced infiltration of the spinal cord with CCR7+ T-cells, an increase of CD25+ T-cells and reduced upregulation of CXCL9 and 10, CCL11 and 12. The data show that CCL21 and CXCR3 have dichotomous functions in traumatic and EAE-evoked neuropathic pain suggesting diverse mechanisms likely requiring diverse treatments although both types of neuropathic pain are mediated in part through the immune activation.Brain Behavior and Immunity 04/2013; · 4.72 Impact Factor -
Article: Inhibition of GTP cyclohydrolase attenuates tumor growth by reducing angiogenesis and M2-like polarization of tumor associated macrophages.
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ABSTRACT: GTP cyclohydrolase (GCH1) is the key-enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. The byproduct, neopterin is increased in advanced human cancer and used as cancer-biomarker, suggesting that pathologically increased GCH1 activity may promote tumor growth. We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. In nude mice xenografted with HT29-Luc colon cancer cells GCH1 inhibition reduced tumor growth and angiogenesis, determined by in vivo luciferase and near-infrared imaging of newly formed blood vessels. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor-attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS-induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1-deficient HT29-Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response.International Journal of Cancer 06/2012; · 5.44 Impact Factor -
Article: Inhibition of GTP cyclohydrolase reduces cancer pain in mice and enhances analgesic effects of morphine.
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ABSTRACT: Noncoding polymorphisms of the GTP cyclohydrolase gene (GCH1) reduce the risk for chronic pain in humans suggesting GCH1 inhibitors as analgesics. We assessed the effects of the GCH1 inhibitor diaminohydroxypyrimidine (DAHP) on nociception and inflammation in a mouse melanoma and a sarcoma cancer pain model, and its co-effects with morphine in terms of analgesic efficacy and respiratory depression. GCH1 inhibition did not reduce the tumor-evoked nociceptive hypersensitivity of the tumor-bearing paw. However, DAHP reduced melanoma- and sarcoma-evoked systemic hyperalgesia as determined by analyzing contralateral paws. GCH1 inhibition increased the inflammatory edema and infiltration with polymorphonuclear leukocytes surrounding the tumor but reduced the tumor-evoked microglia activation in the spinal cord suggesting that an increase of the local immune attack against the tumor may avoid general pain hypersensitivity. When used in combination with morphine at high or low doses, GCH1 inhibition increased and prolonged the analgesic effects of the opioid. It did not, however, increase the respiratory depression caused by morphine. Conversely, the GCH1-product, tetrahydrobiopterin, caused hyperalgesia, antagonized antinociceptive effects of morphine, and aggravated morphine-evoked respiratory depression, the latter mimicked by a cGMP analog suggesting that respiratory effects were partly mediated through the BH4-NO-cGMP pathway. The observed effects of GCH1 inhibition in the tumor model and its enhancement of morphine-evoked antinociception without increase of morphine toxicity suggest that GCH1 inhibitors might be useful as co-therapeutics for opioids in cancer patients.Journal of Molecular Medicine 06/2012; · 4.67 Impact Factor -
Article: Activation of epithelial STAT3 regulates intestinal homeostasis.
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ABSTRACT: The intestinal epithelium that lines the mucosal surface along the GI-tract is a key player for the intestinal homeostasis of the healthy individual. In case of a mucosal damage or a barrier defect as seen in patients with inflammatory bowel disease, the balance is disturbed, and translocation of intestinal microbes to the submucosa is facilitated. We recently demonstrated a pivotal role of STAT3 activation in intestinal epithelial cells (IEC) for the restoration of the balance at the mucosal surface of the gut in an experimental colitis model. STAT3 was rapidly induced in intestinal epithelial cells upon challenge of mice in both experimental colitis and intestinal wound healing models. STAT3 activation was found to be dispensable in the steady-state conditions but was important for efficient regeneration of the epithelium in response to injury. Here, we extend our previous findings by showing epithelial STAT3 activation in human patients suffering from IBD and provide additional insights how the activation of epithelial STAT3 by IL-22 regulates intestinal homeostasis and mucosal wound healing. We also demonstrate that antibody-mediated neutralization of IL-22 has little impact on the development of experimental colitis in mice, but significantly delays recovery from colitis. Thus, our data suggest that targeting the STAT3 signaling pathway in IEC is a promising therapeutic approach in situations when the intestinal homeostasis is disturbed, e.g., as seen in Crohn's disease or Ulcerative colitis.Cell cycle (Georgetown, Tex.) 02/2010; 9(4):652-5. · 5.36 Impact Factor -
Article: Inhibitor kappaB Kinase beta deficiency in primary nociceptive neurons increases TRP channel sensitivity.
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ABSTRACT: Inhibitor kappaB kinase (IKK) regulates the activity of the transcription factor nuclear factor-kappa B that normally protects neurons against excitotoxicity. Constitutively active IKK is enriched at axon initial segments and nodes of Ranvier (NR). We used mice with a Cre-loxP-mediated specific deletion of IKKbeta in sensory neurons of the dorsal root ganglion (SNS-IKKbeta(-/-)) to evaluate whether IKK plays a role in sensory neuron excitability and nociception. We observed increased sensitivity to mechanical, cold, noxious heat and chemical stimulation in SNS-IKKbeta(-/-) mice, with normal proprioceptive and motor functions as revealed by gait analysis. This was associated with increased calcium influx and increased inward currents in small- and medium-sized primary sensory neurons of SNS-IKKbeta(-/-) mice during stimulation with capsaicin or Formalin, specific activators of transient receptor potentials TRPV1 and TRPA1 calcium channels, respectively. In vitro stimulation of saphenous nerve preparations of SNS-IKKbeta(-/-) mice showed increased neuronal excitability of A- and C-fibers but unchanged A- and C-fiber conduction velocities, normal voltage-gated sodium channel currents, and normal accumulation of ankyrin G and the sodium channels Nav1.6 at NR. The results suggest that IKKbeta functions as a negative modulator of sensory neuron excitability, mediated at least in part by modulation of TRP channel sensitivity.Journal of Neuroscience 10/2009; 29(41):12919-29. · 7.11 Impact Factor
