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4. Formylpeptide receptor FPR and the rapid growth of malignant human gliomas

Author

Zhou, Ye, Bian, Xiuwu, Le, Yingying, Gong, Wanghua, Hu, Jinyue, Zhang, Xia, Wang, Lihua, Iribarren, Pablo, Salcedo, Rosalba, Howard, O.M. Zack, Farrar, William, and Wang, Ji Ming

Subjects
G proteins -- Research, Gliomas -- Diagnosis, Gliomas -- Care and treatment, Cancer -- Research, Oncology, Experimental, Health
Abstract

Background: The formylpeptide receptor (FPR) is a G-protein-coupled receptor (GPCR) that mediates chemotaxis of phagocytic leukocytes induced by bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF). We previously showed that selected human glioma cell lines also express functional FPR. We therefore investigated the relationship between FPR expression and the biologic behavior of glioma cells. Methods: Expression and function of FPR in the human glioblastoma cell line U-87 were examined by reverse transcription-polymerase chain reaction (RT-PCR) and chemotaxis assays, respectively. FPR protein expression was detected in specimens from 33 human primary gliomas by immunohistochemistry. FPR short interfering (si) RNA was used to block FPR expression in U-87 cells. Cell proliferation was assessed by measuring DNA synthesis. Xenograft tumor formation and growth were measured in nude mice. Endogenous FPR agonist activity released by necrotic tumor cells was assessed by measuring FPR activation in an FPR-transfected basophil leukemia cell line and live U-87 cells. Vascular endothelial growth factor (VEGF) mRNA was assessed by RT-PCR, and VEGF protein was assessed by enzyme-linked immunosorbent assay. All statistical tests were two-sided. Results: FPR was selectively expressed by the highly malignant human glioblastoma cell line U-87 and most primary grade IV glioblastomas multiforme and grade III anaplastic astrocytomas. U-87 cells responded to the FPR agonist fMLF by chemotaxis (i.e., increased motility), increased cell proliferation, and increased production of VEGF protein. FPR siRNA substantially reduced the tumorigenicity of U-87 cells in nude mice (38 days after implantation, mean tumor volume from wild-type U-87 cells = 842 [mm.sup.3], 95% confidence interval [CI] = 721 to 963 [mm.sup.3]; and from FPR-siRNA transfected U-87 cells = 225 [mm.sup.3], 95% CI = 194 to 256 [mm.sup.3]; P = .001). Necrotic glioblastoma cells released a factor(s) that activated FPR in live U-87 cells. Conclusions: FPR is expressed by highly malignant human glioma cells and appears to mediate motility, growth, and angiogenesis of human glioblastoma by interacting with host-derived agonists. Thus, FPR may represent a molecular target for the development of novel antiglioma therapeutics.

Published
2005

5. Soluble tumor necrosis factor receptor: inhibition of human immunodeficiency virus activation

Author

Howard, O.M. Zack, Clouse, Kathleen A., Smith, Craig, Goodwin, R.G., and Farrar, William L.

Subjects
AIDS (Disease) -- Care and treatment, Tumor necrosis factor -- Physiological aspects, Cell receptors -- Research, HIV (Viruses) -- Research, Science and technology
Abstract

Tumor necrosis factor (TNF) is the primary cytokine which amplifies the expression of type 1 human immunodeficiency virus (HIV-1). The ability of soluble recombinant type I TNF-receptors (TNF-R) of inhibit TNF-alpha-induced HIV-1 expression was investigated. The results showed that a dimer composed of type 1 TNF-R fused to TgG Fc region could restrict the TNF-alpha-induced HIV-1 expression. These results point to the possibility of treating AIDS by limiting the bioactivity of cytokines which enhance the replication and expression of HIV-1.

Published
1993

8. Painful Pathways Induced by Toll-like Receptor Stimulation of Dorsal Root Ganglion Neurons

Author

Qi, Jia, Buzas, Krisztina, Fan, Huiting, Cohen, Jeffrey I., Wang, Kening, Mont, Erik, Klinman, Dennis, Oppenheim, Joost J., and Howard, O.M. Zack

Subjects
Polyunsaturated Alkamides, Blotting, Western, Pain, TRPV Cation Channels, Arachidonic Acids, Article, Dinoprostone, Mice, Ganglia, Spinal, Animals, Humans, Anilides, Cells, Cultured, Neurons, Microscopy, Confocal, Dose-Response Relationship, Drug, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptors, Imidazoles, Toll-Like Receptor 3, Poly I-C, Toll-Like Receptor 7, Cinnamates, Toll-Like Receptor 9, Aminoquinolines, Cytokines, Calcium, Capsaicin, Endocannabinoids, Signal Transduction
Abstract

We hypothesize that innate immune signals from infectious organisms and/or injured tissues may activate peripheral neuronal pain signals. In this study, we demonstrated that toll-like receptors 3/7/9 (TLRs) are expressed by human dorsal root ganglion neurons (DRGNs) and in cultures of primary mouse DRGNs. Stimulation of murine DRGNs with TLR ligands induced expression and production of proinflammatory chemokines and cytokines CCL5 (RANTES), CXCL10 (IP10), interleukin-1alpha, interleukin-1beta, and prostaglandin E2 (PGE2), which have previously been shown to augment pain. Further, TLR ligands up-regulated the expression of a nociceptive receptor transient receptor potential vanilloid type 1 (TRPV1), and enhanced calcium flux by TRPV1 expressing DRGNs. Using a tumor-induced temperature sensitivity model, we showed that in vivo administration of a TLR9 antagonist, known as a suppressive ODN, blocked tumor-induced temperature sensitivity. Taken together, these data indicate that stimulation of peripheral neurons by TLR ligands can induce nerve pain.

Published
2011

12. Chemotactic activity of S100A7 (psoriasin) is mediated by RAGE and potentiates inflammation with highly homologous but functionally distinct S100A15

Author

Wolf, Ronald, Howard, O.M. Zack, Dong, Hui-Fang, Voscopoulos, Christopher, Boeshans, Karen, Winston, Jason, Divi, Rao, Gunsior, Michele, Goldsmith, Paul, Ahvazi, Bijan, Chavakis, Triantafyllos, Oppenheim, Joost J, and Yuspa, Stuart H.

Subjects
Inflammation, Keratinocytes, Mice, Knockout, Calcium-Binding Proteins, Receptor for Advanced Glycation End Products, S100 Proteins, Article, Lymphocyte Subsets, S100 Calcium Binding Protein A7, Cell Line, Receptors, G-Protein-Coupled, Chemotaxis, Leukocyte, Mice, Animals, Humans, Receptors, Immunologic
Abstract

Human S100A7 (psoriasin) is overexpressed in inflammatory diseases. The recently discovered, co-evolved hS100A15 is almost identical in sequence and upregulated with hS100A7 during cutaneus inflammation. The functional role of these closely related proteins for inflammation remains undefined. By generating specific antibodies, we demonstrate that hS100A7 and hS100A15 proteins are differentially expressed by specific cell types in the skin. Although highly homologous, both proteins are chemoattractants with distinct chemotactic activity for leukocyte subsets. We define RAGE (receptor of advanced glycated end products) as the hS100A7 receptor, whereas hS100A15 functions through a Gi protein coupled receptor. hS100A7-RAGE binding, signaling and chemotaxis are zinc-dependent in vitro, reflecting the previously reported zinc-mediated changes in the hS100A7 dimer structure. When combined, hS100A7 and hS100A15 potentiate inflammation in vivo. Thus, proinflammatory synergism in disease may be driven by the diverse biology of these almost identical proteins that have just recently evolved. The identified S100A7 interaction with RAGE may provide a novel therapeutic target for inflammation.

Published
2008

15. Histidyl–tRNA Synthetase and Asparaginyl–tRNA Synthetase, Autoantigens in Myositis, Activate Chemokine Receptors on T Lymphocytes and Immature Dendritic Cells

Author

Howard, O.M. Zack, primary, Dong, Hui Fang, additional, Yang, De, additional, Raben, Nina, additional, Nagaraju, Kanneboyina, additional, Rosen, Antony, additional, Casciola-Rosen, Livia, additional, Härtlein, Michael, additional, Kron, Michael, additional, Yang, David, additional, Yiadom, Kwabena, additional, Dwivedi, Sunita, additional, Plotz, Paul H., additional, and Oppenheim, Joost J., additional

Published
2002
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18. In vitro generated Th17 cells support the expansion and phenotypic stability of CD4+Foxp3+ regulatory T cells in vivo.

Author

Zhou, Qiong, Hu, Ya, Howard, O.M. Zack, Oppenheim, Joost J., and Chen, Xin

Subjects
*PHENOTYPES, *CD4 antigen, *T cells, *GENE expression, *FORKHEAD transcription factors, *TUMOR necrosis factor receptors, *CHIMERIC proteins, *LABORATORY mice
Abstract

Highlights: [•] Th17 cells express the highest levels of TNF than other Th subsets. [•] Th17 cells most potently stimulate co-transferred Tregs in Rag1 KO mice. [•] This effect of Th17 cells is TNF- and IL-2-dependent. [•] TNF–TNFR2 plays crucial role in reciprocal stimulation of Th17 cells and Tregs. [Copyright &y& Elsevier]

Published
2014
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