May-June 2008 l Vol 14 l No 5-6

Commentary
The IGF-1 Receptor as a Therapeutic Target to Improve Endothelial Progenitor Cell Function
Felix Fleissner and Thomas Thum
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Gram-Positive and Gram-Negative Bacteria Synergise with Oxidants to Release CXCL8 from Innate Immune Cells
Mark J Paul-Clark, Rosalinda Sorrentino, Lucy K Bailey, Shiranee Sriskandan, and Jane A Mitchell
Inflammation, which occurs in a number of life-threatening diseases, is associated with an increase in oxidant stress. Oxidants can activate monocytes via Toll-Like Receptor (TLR) 2, however, the functional downstream consequence on immune system bacterial surveillance is unknown. Paul-Clark et al. (238-246) investigated the effects of oxidants on activation of human cells derived from smokers and nonsmokers. Blood from smokers was more sensitive to bacterial stimulation than blood from non-smokers, suggesting that oxidant stress associated with smoking provides an initiating inflammatory signal, potentially via TLR2 or associated transduction pathways, which sensitizes cells to pathogenic stimuli. Such a synergistic relationship between oxidants and pathogen-induced cell activation provides insight to inflammation-associated oxidant stress.
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Diversity of Interferon gamma and Granulocyte-Macrophage Colony-Stimulating Factor in Restoring Immune Dysfunction of Dendritic Cells and Macrophages During Polymicrobial Sepsis
Stefanie B Flohé, Hemant Agrawal, Sascha Flohé, Meenakshi Rani, Jörg M Bangen, and F Ulrich Schade
Sepsis is associated with immunosuppression that prevents host development of an effective immune response against invading microorganisms which may lead to unrestricted spreading of bacteria, multiple organ failure and death.  The impaired capacity of dendritic cells to mount a protective T helper cell type (TH1) response contributes to this immunosuppression. Flohé et al. (247-256) investigated the suppressed cytokine secretion pattern of dendritic cells (DC) during sepsis and analyzed immuno- modulatory approaches for restoration of IL-12 secretion, the key cytokine in TH1 cell development. Results show that the development of immunosuppression during sepsis is associated with an impaired capacity of splenic DC and macrophages to release TH1-promoting cytokines upon stimulation with bacterial products. Immunomodulatory cytokines increased IL-12 synthesis by dendritic cells early during sepsis as well as increased the activity of macrophages. Therapies that modulate the dysfunction of dendritic cells might have beneficial effects on the outcome of sepsis.
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Continous Hemodiafiltration with PMMA Hemofilter in the Treatment of Patients with Septic Shock
Taka-aki Nakada, Shigeto Oa, Ken-ichi Matsuda, Tomohito Sadahiro, Masataka Nakamura, Ryuzo Abe, and Hiroyuki Hirasawa
Cytokines play a pivotal role in the complex pathophysiology of severe sepsis and septic shock. While cytokine-targeting treatment modalities for these conditions have been devised and tested, few have exhibited beneficial therapeutic effects. Blood purification, originally developed for the treatment of renal failure, has been applied to critical illnesses. Using polymethylmethacrylate-continuous hemodiafiltration (PMMA-CHDF) to remove cytokines, Nakada et al. (257-263) improved hypercytokinemia and dysoxia in patients with septic shock. Their findings suggest that cytokine-oriented therapy using PMMA-CHDF may be an effective strategy for treatment of septic shock.
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Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas
Linda Yu, Katrin Saile, Carol D Swartz, Hong He, Xiaolin Zheng, Grace E Kissling, Xudong Di, Shantelle Lucas, Stanley J Robboy, and Darlene Dixon
Uterine leiomyomas (fibroids) are benign neoplasms of the myometrium prevalent in reproductive-aged women. While some leiomyomas are asymptomatic, others cause pelvic pain, menstrual bleeding and infertility. Surgery remains the gold standard of treatment but is a costly and invasive option. Receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in leiomyomas and in this work, Yu et al. (264-275) used a phospho-RTK array technique to detect RTK activity in leiomyomas. Analysis revealed that overexpression of RTKs and activation of the IGF-IR signaling pathway are important mediators of uterine leiomyoma growth. These data may provide new anti-tumor targets for noninvasive treatment of leiomyomas.
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Molecular Pathways Involved in Loss of Kidney Graft Function with Tubular Atrophy and Interstitial Fibrosis
Daniel G Maluf, Valeria R Mas, Kellie J Archer, Kenneth Yanek, Eric M Gibney, Anne L King, Adrian Cotterell, Robert A Fisher, and Marc P Posner
With close to 5,000 kidney transplants failing per year in the US returning the recipients to dialysis, kidney transplant failure is a leading cause of end-stage renal disease. Loss of kidney graft function with tubular atrophy (TA) and interstitial fibrosis (IF), a set of findings termed chronic allograft nephropathy (CAN), causes most kidney allograft losses. Maluf et al. (276-285) identified several molecular pathways involved in TA/IF progression.  A distinctive gene expression pattern was observed in TA/IF subjects when compared with normal allografts and kidneys.  Altered gene expression in networks related to immune response, inflammation and cell-to-cell interaction highlight the importance of chronic inflammation in progressive graft deterioration and may lead to the identification of biomarkers or predictors of TA/IF and long term graft function.
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Supplementary Data 1: PDF (304 KB)
Supplementary Data 2: PDF (180 KB)

Unusual Phenotypic Features in a Patient with a Novel Splice Mutation in the GHRHR Gene
Latifa Hilal, Yassir Hajaji, Marie-Pierre Vie-Luton, Zeina Ajaltouni, Bouchra Benazzouz, Maha Chana, Adelmajid Chraïbi, Abdelkrim Kadiri, Serge Amselem, and Marie-Laure Sobrier
Isolated growth hormone deficiency (IGHD), which can result from altered pituitary functions, may be of genetic origin. To date, five genes have been linked to IGHD, one of which encodes the growth hormone releasing hormone receptor (GHRHR). GHRHR plays a pivotal role in growth hormone synthesis and secretion by the pituitary. In this work, Hilal et al. (286-292) describe the particular phenotypes of two siblings with IGHD, born to a consanguineous union, in whom a novel splice site mutation in the GHRHR gene was identified. These observations broaden the phenotype associated with GHRHR defects and the authors discuss a possible role of GHRHR in the development of extrapituitary structures.
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Several Regions in the Major Histocompatibility Complex Confer Risk for Anti-CCP-Antibody Positive Rheumatoid Arthritis, Independent of the DRB1 Locus
Hye-Soon Lee, Annette T Lee, Lindsey A Criswell, Michael F Seldin, Christopher I Amos, John P Carulli, Cristina Navarrete, Elaine F Remmers, Daniel L Kastner, Robert M Plenge, Wentian Li, and Peter K Gregersen
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation and progressive joint destruction. Recently, several new genes with modest levels of risk for RA have been identified in various populations. Nevertheless, the MHC remains the strongest region of genetic association with this disease, and until recently this has been assumed to be entirely due to the well-defined allelic associations with the class II HLA-DRB1 locus. However, it is likely that additional risk loci for RA are present WITHIN the major histocompatibility complex (MHC), independent of the HLA-DRB1 locus. Lee et al. (293-300) now provide evidence for several new risk loci for RA located in the Class I region of the MHC, as well as in the region centromeric to the DRB1 locus. These data emphasize the need for more detailed analysis of the MHC in RA, a theme that is also emerging for other autoimmune diseases such as type 1 diabetes.
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Supplementary Data: PDF (412 KB)

Insulin Stimulates the Clonogenic Potential of Angiogenic Endothelial Progenitor Cells by IGF-1 Receptor-Dependent Signaling
Per M Humpert, Zdenka Djuric, Ulf Zeuge, Dimitrios Oikonomou, Yuri Seregin, Klaus Laine, Volker Eckstein, Peter P Nawroth, and Angelika Bierhaus
Endothelial progenitor cells (EPC) are involved in vascular regeneration and angiogenesis in experimental diabetes. Insulin therapy mobilizes circulating progenitor cells and in this work Humpert et al.(301-308) examined the effects of insulin on EPC outgrowth in blood from patients with type 2 diabetes. Results show the insulin-like growth factor 1 (IGF-1) receptor mediated the effect of insulin on EPC growth, which was in part dependent on MAP kinases. Insulin-mediated activation of the IGF-1 receptor led to increased clonogenic and angiogenic potential of EPCs in vitro. Specific therapeutic modulation of this signaling pathway may offer potential targets for the treatment of vascular diabetic complications.
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Apoptosis in Transgenic Mice Expressing the P301L Mutated Form of Human Tau
Rita M Ramalho, Ricardo J S Viana, Rui E Castro, Clifford J Steer, Walter C Low, and Cecilia M P Rodrigues
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by extracellular plaques of amyloid β and intracellular aggregations of tau. While the exact role of cell death is unclear, apoptosis is increased and caspase-3 is activated in AD. Ramalho et al. (309-317) examined the role of apoptosis in neuronal loss and tau pathology in a mouse model of tauopathy. Results showed that caspase-3 cleaved intermediate tau species early in the course of the disease, and preceded cell loss in amyloid β-exposed cultured neurons. The authors suggest a potential role for apoptosis in neuro- degeneration and underscore the importance of antiapoptotic agents in treating neurodegeneration associated with AD and other tauopathies.
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Expression of Odontogenic Ameloblast-Associated Protein (ODAM) in Dental and Other Epithelial Neoplasms
Daniel P Kestler, James S Foster, Sallie D Macy, Charles L Murphy, Deborah T Weiss, and Alan Solomon
Odontogenic ameloblast-associated protein (ODAM) is highly expressed by mature ameloblasts and is present in the enamel organ and junctional epithelial cells of the teeth. In addition to the role of ODAM in odontogenesis, ODAM is upregulated in human cervical and gastric cancer. Kestler et al. (318-326) generated anti-ODAM antibodies to gain further insight into the potential role of ODAM in tissue development and carcinogenesis. The ODAM-specific antibodies recognize ODAM molecules in ameloblasts, as well as certain normal and neoplastic human epithelial tissues. The results indicate that ODAM is a developmental antigen with an essential role in tooth maturation as well as in the pathogenesis of certain odontogenic and other epithelial neoplasms. ODAM may serve as a prognostic biomarker and a potential diagnostic and therapeutic target for patients with breast and other epithelial forms of cancer.
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Molecular Events in the Cardiomyopathy of Sepsis
Michael A Flierl, Daniel Rittirsch, Markus S Huber-Land, J Vidya Sarma, and Peter A Ward
Septic cardiomyopathy is a well-described complication of severe sepsis and
septic shock. However, the interplay of its underlying mechanism remains enigmatic. Flierl et al. (327-336) describe the present understanding of systemic, supracellular and molecular mechanisms involved in sepsis-induced myocardial suppression.
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Molecular Mediators of Liver Ischemia and Reperfusion Injury: A Brief Review
Andrew J Vardanian, Ronald W Busuttil, and Jerzy W Kupiec-Weglinski
Ischemia and reperfusion injury represents a complex series of events that result in cellular and tissue damage. Vardanian et al. (337-345) describe the current understanding of molecular mechanisms involved in ischemia and reperfusion injury, primarily in the liver, and their putative therapeutic implications.
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Functional Consequences of Toll-like Receptor 4 Polymorphisms
Bart Ferwerda, Matthew BB McCall, Karlijn Verheijen, Bart-Jan Kullberg, André JAM van der Ven, Jos WM Van der Meer, and Mihai G Netea
The innate immune system recognizes a broad range of pathogens and initiates protective responses. Toll-like receptor 4 (TLR4) is an important pathogen recognition receptor that binds lipopolysaccharide of Gram-negative bacteria, structures from fungal and mycobacterial pathogens, and endogenous ligands. Two nonsynonymous polymorphisms of TLR4 may alter the function of the receptor. Ferwerda et al. (346-352) compare studies that assessed the effect of these polymorphisms on susceptibility to Gram-negative infections, and examine the phenotypic consequences of these polymorphisms. In addition, the geographical distribution of the TLR4 polymorphisms is reviewed, and a model for the evolutionary pressures on the TLR4 genetic make-up is presented.
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Zinc in Human Health: Effect of Zinc on Immune Cells
Ananda S Prasad
Although zinc requirements for plants and animals have been long-known, the role of zinc in human physiology has only recently been recognized. Zinc deficiency is prevalent in the developing world and is responsible for growth retardation in as many as two billion people. In this review, Dr. Prasad (353-357) reviews the evidence that zinc deficiency can lead to immune dysfunction, cognitive impairment, bullous pustular dermatitis, alopecia, diarrhea, weight loss, and a host of other complications.
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