Cytokine Bulletin Spring | 2007 Cytokine BULLETIN

R&D Systems Cytokine Bulletin spring | 2007 cytokine BULLETIN Inside page 2 MMP-12 in Smoking-Related Pulmonary Disease page 3 Regulation of VE-Cadherin & VEGF R2 by VEGF page 4 Sonic Hedgehog A morphogen involved in axon guidance BIObrief Mini-Poster Integrin Subunit Interactions page 5 RECENT CITATIONS Leptin & Leptin Receptor page 6 How to Find Figure 1. Hypothesized mechanism of Notchmediated neural stem cell expansion in vivo, based on infusion of soluble Notch ligand in the rat model. In vitro studies in fetal neural stem cells show that Notch activation by DLL4 induces a cytoplasmic signaling Technical Information cascade that preserves fetal neural stem cell pluripotency and encourages cell expansion through STAT3dependent Sonic hedge @ www.RnDSystems.com hog (Shh) release. (adapted from reference 4) MEETINGS Taking Advantage of Notch in Stem Cell Expansion page 7 The future utilization of stem cell therapy for AndroutsellisTheotokis and colleagues outlined NEW TOOLS neurodegenerative disease has been impeded by a signaling cascade initiated by Notch ligands, Recombinant Proteases the limited numbers of stem cells that can be gen Deltalike 4 (DLL4) and Jagged 1 (Jag1), that of the Renin-Angiotensin erated in vitro for transplantation, the potential increased fetal neural stem cell (NSC) survival System (RAS) immune response to the transplanted cells, and without inducing differentiation in vitro.4 This the sparse population of endogenous progenitor pathway includes the obligate cleavage of Nicd. page 8 cells that exist in vivo. Thus, in addition to mas However, the rapid timeline of cell expansion TECHNICAL NOTES tering the isolation and molecular guidance of indicates that Nicd influences cytoplasmic Assessing the Pluripotent stem cells, research is focusing on understanding effectors rather than, or in addition to, the Status of Stem Cells mechanisms that increase stem cell numbers and commonlyassociated yet delayed transcriptional survival, and minimize host rejection. response. Examination of kinase activation and Notch encodes a transmembrane receptor with administration of JAK and p38 kinase inhibitors signaling integral to development and cancer. identified that DLL4 and Jag1 led to activation of Akt kinase and mammalian target of rapamycin Tools for Cell Biology Research Notch signaling occurs through ligandinduced cleavage that frees the Notch intracellular do (mTOR). Both are serine/threonine kinases re main (Nicd) to enter the nucleus and alter gene lated to cell proliferation and differentiation, with expression via tissuespecific transcription fac downstream phosphorylation of transcription tors.1 Among numerous roles in nervous system factor STAT3. development, Notch is imperative in stem cell Other research has associated Notch signaling biology because its signaling maintains an un and STAT3 activation with differentiation to a differentiated progenitor population.2,3 However, glial cell fate.57 This is in apparent contrast to a the exact mechanism by which Notch prevents Notchdependent preservation of pluripotency. differentiation to prolong selfrenewal and pluri The discrepancy may be explained by different potency, and its manipulation for therapeutic phosphorlyation sites. Rather than the previously applications, has only recently been proposed reported phosphorlyation of STAT3 (Tyr705) that ® (Figure 1). drives glial cell fate, 7 AndroutsellisTheotokis et al. Notch continued on page 5 MMP-12 in Smoking-Related Pulmonary Disease Chronic obstructive pulmonary disease (COPD), the fifth leading Some elements of COPD pathogenesis precede macrophage or cause of death worldwide, is estimated by the World Health Organ neutrophil accumulation. Studies on airway cells in vitro bypass the ization (WHO) to affect 80 million people.1 Cigarette smoking is the influence of inflammatory cells and show direct effects of smoke or major risk factor for COPD, which includes both emphysema and smoke condensates. For example, the oxidative effects of smoke chronic bronchitis, also called small airway disease. In emphysema, induce MMP12 expression via a TNFadependent pathway in peripheral air spaces in the lung are enlarged and walls of bronchioles cultured airwaylike epithelia.7 Oxidants are also involved in release and alveoli are destroyed. Chronic bronchitis, which may occur con of TGFb from latency in tracheal explants.8 Active TGFb is likely to currently with emphysema, includes airway wall repairinduced fi mediate fibrogenic airway remodeling, an effect that is blocked in brosis.1 Inflammation, proteinase imbalance, oxidative stress, and MMP12deficient mice.8 Similarly, apoptotic pathways induced by apoptosis all appear to be interwoven in the pathogenesis of COPD, either TGFb or Fas (CD95) may cause lung fibrosis that can be and the matrix metalloproteinase MMP12 plays a role in each of ameliorated by deletion of MMP12.9,10 Human airway smooth muscle these processes (Figure 1). cells have also been shown to contribute active MMP12 in response to IL1b a 11 Disruption of the balance between proteolytic enzymes, such as elas and TNF . tases and their inhibitors, has long been considered the major cause A pivotal study showed that deletion of mouse MMP12 abrogates of COPD.2 This proteaseantiprotease imbalance is now thought to development of cigarette smokeinduced COPD.12 Since then, other be caused by chronic inflammation.2 Macrophage elastase MMP12 studies have shown that deletion or inhibition of neutrophil elastase, (inhibited by TIMP1) and neutrophil elastase (inhibited by a1 TGFb, or TNFa substantially reduces lung damage in response to antitrypsin) are the most abundant elastases in the lung. TNFa, which cigarette smoke.3,4,7,8,13 Conversely, naturally occurring human de is released from the cell membrane by MMP12, is the major recruiter ficiency of a1antitrypsin, the major human inhibitor of neutrophil of neutrophils to the lung; IFNg also recruits neutrophils and stim elastase, confers susceptibility to COPD.1, 2 It is clear that the entire ulates MMP12 activity.24 Once present, neutrophil elastases and story of COPD pathogenesis involves these and other players in a oxidants secreted in the inflammatory environment mediate much of complex, interwoven cascade. The development of COPD in response the destruction of lung tissue.5 Elastin fragments are also chemotactic, to cigarette smoke is not universal and, when it does occur, varies in recruiting monocytes that differentiate to form alveolar macrophages time of onset for both humans and rodent strains.1,2 This variation that comprise the bulk of the inflammatory cells accumulating in the likely results from interaction of genetic influences with environment. interstitium, septum, and alveolar airspaces in emphysema.6 One example is the increased susceptibility to COPD in smokers that have specific polymorphisms in both human MMP1 and MMP12.14 References Irritants 1. GOLD Executive Summary (2006) http://www.goldcopd.com Oxidants 2. Elias, J. A. et al. (2006) Proc. Am. Thorac. Soc. 3:494. Monocytes 3. Churg, A. et al. (2003) Am. J. Respir. Crit. Care Med. 167:1083. Cigarette Smoke Elastin Fragments 4. Churg, A. et al. (2004) Am. J. Respir. Crit. Care Med. 170:492. 5. Lucattelli, M. et al. (2005) Respir. Res. 6:83. 6. Houghton, A. M. et al. (2006) J. Clin. Invest. 116:753. 7. Lavigne, M. C. & M. J. Eppihimer (2005) Biochem. Biophys. Res. Alveoloar TNF-α Commun. 330:194. MMP-12 Macrophages TNF-α 8. Wang, R. D. et al. (2005) Am. J. Respir. Cell Mol. Biol. 33:387. release 9. Kang, H.R. et al. (2007) J. Biol. Chem. 282:7723. 10. MatuteBello, G. et al. (2007) Am. J. Respir. Crit. Care Med., April 9 TIMP-1 Smooth Muscle α-1-AT [Epub ahead of print] and Epithelial tissue 11. Xie, S. et al. (2005) Respir. Res. 6:148. Neutrophils 12. Hautamaki, R. D. et al. (1997) Science 227:2002. TGF-β activation 13. Wright, J. L. et al. (2007) Am. J. Physiol. Lung Cell Mol. Physiol. Neutrophil 292:L125. Apoptosis Elastase 14. Joos, L. et al. (2002) Hum. Mol. Genet. 11:569. Airway repair and remodeling This symbol denotes references that cite the use of our products. Fibrogenesis Airway Damage Figure 1. MMP12 is produced by alveolar macrophages, smooth Chronic Bronchitis Emphysema muscle cells, and epithelia in response to cigarette smoke. It is a key molecule in the recruitment of inflammatory cells, release of TNFa, and pathways downstream of TGFb activation. These activities lead to the airway damage, fibrogenesis, repair, and remodeling that are the hall marks of COPD. COPD 2 For research use only. Not for use in diagnostic procedures. Regulation of VE-Cadherin and VEGF R2 by VEGF VECadherin and VEGF R2 are transmembrane It was recently reported that VEGF R2 signal adhesion.8 TNFa also promotes vascular glycoproteins that are expressed in the ad ing is enhanced by endocytosis. Interesting permeability by inducing Fyndependent herens junctions between vascular endo ly, VECadherin was shown to play an inhibit tyrosine phosphorylation of VECadherin.9 thelial cells (EC). VECadherin interacts ho ory role in this process. By binding to VEGF Lastly, exposure of endothelium to oxidized mophilically between neighboring cells to R2, VECadherin prevents VEGF R2 en LDL promotes VECadherin internalization provide strength to the endothelium. VE docytosis. This favors inactivation by a junc and increased monocyte transendothelial Cadherin adhesion is reduced during angio tionassociated, transmembrane tyrosine migration.10 phosphatase, called DEP1.5 genesis and leukocyte extravasation, two When clathrin These advances in the understanding of the processes that require decreased EC attach dependent internalization transports phos interactions between VECadherin and VEGF ment. It is well established that adherens phorylated VEGF R2 to endosomal vesicles, R2 clarify how the adherens junction is junction integrity is regulated by VECadher uninterrupted VEGF R2 signaling is made regulated in response to VEGF stimulation.

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