Arginase: marker, effector, or candidate for ?

Donata Vercelli

J Clin Invest. 2003;111(12):1815-1817. https://doi.org/10.1172/JCI18908.

Commentary

Microarray analysis of the expression profiles of lung tissue in two murine models of asthma revealed high levels of I and arginase II activity, in association with IL-4 and IL-13 overexpression, suggesting that pathways are critical in the pathogenesis of asthma.

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Arginase: marker, effector, or candidate and collaborators (2), who determined transcript expression profiles in lung tis- gene for asthma? sue from mice with an asthma-like phe- notype induced by sensitization with Donata Vercelli OVA or Aspergillus fumigatus. The recog- nized strength of microarray experi- Arizona Respiratory Center, College of Medicine, University of Arizona, ments lies in their ability to address an Tucson, Arizona, USA issue globally, and highlight the unex- pected. The results of this study are no Microarray analysis of the expression profiles of lung tissue in two exception. An important quantitative murine models of asthma revealed high levels of arginase I and arginase finding was that 6.5% of the 12,422 II activity, in association with IL-4 and IL-13 overexpression (see the analyzed showed a greater than related article beginning on page 1863), suggesting that arginine path- twofold change in expression in chal- ways are critical in the pathogenesis of asthma. lenged mice. These data show that, although asthma remains confined to J. Clin. Invest. 111:1815–1817 (2003). doi:10.1172/JCI200318908. the lung, the mechanistic dysregulation underlying the disease — whatever that Despite intense research efforts, asthma asthma (1). The reasons why asthma may be — mobilizes a vast genetic pro- remains a major medical and scientific prevalence has been on the rise for so gram. Even more importantly, among challenge. Prevalence of this disease long remains a matter of intense specu- the 496 and 527 genes identified in the increased 75% between 1980 and 1998. lation. The pathogenetic mechanisms of OVA and Aspergillus models, respective- Although this rate may now be stabiliz- the disease, and the contributing genet- ly, only 291 were common to both. ing, the 2001 National Health Interview ic factors, also remain elusive. This state Since all mice had the same genetic Survey estimated that 6.9% of adults, of affairs probably reflects the inherent background, this pattern is likely to and 8.9% of children under the age of complexity of the disease, and the diffi- result from differences in pathogenetic 18 in the United States, suffered from culty associated with stringently defin- mechanisms, possibly related to the ing asthmatic phenotypes so that nature of the allergen and/or the Address correspondence to: Donata Vercelli, homogenous subject groups can be immunization route. Such data should College of Medicine, University of Arizona, 1501 North Campbell Avenue, Suite 2349, identified for mechanistic studies. provide molecular epidemiologists and Tucson, Arizona 85724-5030, USA. clinicians interested in asthma with Phone: (520) 626-6387; Fax: (520) 626-6970; Microarrays: a powerful tool spicy food for thought. E-mail: [email protected]. to dissect asthma Conflict of interest: The author has declared that no conflict of interest exists. An aggressive approach to the identifi- Enter arginine and its pathways Nonstandard abbreviations used: protein cation of new asthma genes is discussed Intriguing findings also came from the inhibitor of activated STAT1 (PIAS1). in this issue of the JCI by Zimmermann qualitative analysis of lung transcript

The Journal of Clinical Investigation | June 2003 | Volume 111 | Number 12 1815 expression of arginase, but not NO , was altered in the lungs of the allergen-challenged mice (2). Last, but not least, at the molecular level, arginine appears to be a key reg- ulator of signaling through the JAK/STAT pathway. Indeed, post- translational modification (methyla- tion) of a highly conserved arginine residue in the N-terminal domain of STAT1 is a requirement for IFN-α– and IFN-β–induced transcription (10). In the absence of arginine methyla- tion, STAT1-DNA binding is impaired due to an increased association of Figure 1 the protein inhibitor of activated Arginine, arginase, and asthma. Arginase I and arginase II control the transformation of arginine STAT1 (PIAS1) (11) with phosphory- into , which in turn gives rise to proline and polyamines. These products have multiple lated STAT1 dimers. No STAT6-spe- effects on connective tissue, , and mucus synthesis. Arginine also serves as a sub- cific PIAS has been identified to date, strate for NO synthase (NOS), which generates NO, a critical regulator of airway physiology. The but the negative regulation of STAT NOS and arginase pathways interfere with each other through substrate competition. Th2 cytokines induce arginase expression. During allergic inflammation, increased IL-4 and/or IL-13 signaling is expected to involve more expression results in increased expression of arginase and amplification of the arginase-depend- than one member of the PIAS family. ent pathway, with concomitant suppression of NO generation. This leads to airway hyperre- The search is on, and may well be sponsiveness and increased generation of mucus and collagen, all of which may contribute to successful. the pathogenesis of asthma. The red arrows mark the upregulatory or downregulatory events that occur in arginine following increased expression of Th2 cytokines. A novel asthma gene? The study by Zimmermann et al. (2) confirms that expression of arginase profiles. The genes differentially ex- with one another through substrate is increased in the asthmatic lung pressed in challenged mice included ar- competition (3). NO is a ubiquitous through a Th2-induced, STAT6-de- ginase I, arginase II, and the L-arginine gaseous molecule that regulates pendent mechanism, and most im- transporter cationic amino acid trans- many aspects of human airway biolo- portantly extends these findings to porter-2. All of these molecules are in- gy, including airway and vascular humans. Interestingly, in situ hy- volved in arginine metabolism (Figure smooth muscle tone (4). An increased bridization in the lung of asthmatic 1). In particular, arginase catalyzes the concentration of NO in exhaled air is patients revealed expression of ar- hydrolysis of arginine to ornithine and now recognized as a critical compo- ginase not only in submucosal in- , and exists in two isoforms. Argin- nent of the asthmatic phenotype (5). flammatory cells (most likely ma- ase I participates in the ,and is The links with the NO pathway and crophages, as observed in the murine expressed at high levels in the liver. collagen generation make arginine model) but also in airway epithelium, Arginase I deficiencyresults in arginine- metabolism a rising star in the asth- suggesting an even broader pattern mia, a disorder characterized by mental ma firmament. Arginase I and argi- of dysregulation. In the scenario pro- impairment, growth retardation, spas- nase II were recently shown to con- posed by Zimmermann and collabo- ticity, and sometimes fatal episodes of tribute to the development of mouse rators, a Th2 cytokine-dependent hyperammonemia. Arginase II is most lung fibrosis (6). Increased arginase increase of arginase expression in the highly expressed in the prostate and activity underlies allergen-induced lung would affect arginine me- kidney, and poorly expressedin the liver. deficiency of NO and airway hyperre- tabolism, and contribute to asthma Arginase II is thought to be involved in sponsiveness in a guinea pig model of pathogenesis through inhibition of the synthesis of proline and/or poly- allergic asthma (7). Perhaps even NO generation and alterations of cell amines (e.g., putrescine, spermidine, more importantly, arginase expres- growth and collagen deposition. and spermine), which control cell pro- sion appears to be controlled by Th2 Thus, arginase would act as an effec- liferation and collagen production. To cytokines, central mediators of aller- tor of Th2 activation. The available date, no human disease has been associ- gic asthma (8). IL-13–mediated in- arginase I and arginase II knock-out ated with a deficiency in arginase II (3). duction of arginase I in mice (12, 13), and conditional and/or has been implicated in IL-13–de- tissue-specific knockouts generated Arginine, a molecule of many trades pendent inhibition of NO produc- ad hoc, may serve to highlight the Of note, arginine serves as a substrate tion (9), which in turn may contri- effector role of arginase. The real for both arginase and NO synthase bute to asthma pathogenesis. We may question, however, is whether argi- (Figure 1). The arginase and NO syn- infer that NO inhibition resulted nase will make it onto the list of asth- thase pathways can therefore interfere from substrate competition, because ma genes. The attribution of a

1816 The Journal of Clinical Investigation | June 2003 | Volume 111 | Number 12 causative role to arginase will de- esis. J. Clin. Invest. 111:1863–1874. vascular smooth muscle cells. Am. J. Physiol. Cell. doi:10.1172/JCI200317912. Physiol. 279:C248–C256. pend on the results of the genetic 3. Morris, S.M., Jr. 2002. Regulation of of 9. Chang, C., Zoghi, B., Liao, J.C., and Kuo, L. 2000. studies that Zimmermann and col- the urea cycle and arginine metabolism. Annu. The involvement of kinases, cyclic leagues’ work warrants. Do single Rev. Nutr. 22:87–105. AMP/protein kinase A, and p38 mitogen-activat- 4. Fischer, A., Folkerts, G., Geppetti, P., and ed protein kinase in IL-13-mediated arginase I nucleotide polymorphisms in hu- Groneberg, D.A. 2002. Mediators of asthma: induction in macrophages: its implications in man arginase dysregulate expression . Pulm. Pharmacol. Ther. 15:73–81. IL-13-inhibited nitric oxide production. J. Immunol. 5. Wechsler, M.E., et al. 2000. in 165:2134–2141. and/or function so as to contribute patients with asthma: association with NOS1 geno- 10. Mowen, K.A., et al. 2001. Arginine methylation of to asthma pathogenesis? The role of type. Am. J. Respir. Crit. Care Med. 162:2043–2047. STAT1 modulates IFNalpha/beta-induced tran- arginase in the realm of asthma will 6. Endo, M., et al. 2003. Induction of arginase I and scription. Cell. 104:731–741. II in bleomycin induced fibrosis of mouse lung. 11. Liu, B., Gross, M., ten Hoeve, J., and Shuai, K. ultimately be dictated by the answer Am. J. Physiol. Lung Cell. Mol. Physiol. doi:10.1152/ 2001. A transcriptional corepressor of Stat1 with to this question. ajplung.00434.2002. an essential LXXLL signature motif. Proc. Natl. 7. Meurs, H., et al. 2002. Increased arginase activity Acad. Sci. U. S. A. 98:3203–3207. 1. 2003. Asthma Prevalence, Health Care Use and Mor- underlies allergen-induced deficiency of cNOS- 12. Shi, O., Morris, S.M.J., Zoghbi, H., Porter, C.W., and tality, 2000-2001. National Center for Health Sta- derived nitric oxide and airway hyperresponsive- O’Brien, W.E. 2001. Generation of a mouse model tistics, Center for Disease Control. ness. Br. J. Pharmacol. 136:391–398. for arginase II deficiency by targeted disruption of 2. Zimmermann, N., et al. 2003. Dissection of 8. Wei, L.H., Jacobs, A.T., Morris, S.M.J., and Ignar- the arginase II gene. Mol. Cell. Biol. 21:811–813. experimental asthma with DNA microarray ro, L.J. 2000. IL-4 and IL-13 upregulate arginase I 13. Iyer, R.K., et al. 2002. Mouse model for human analysis identifies arginase in asthma pathogen- expression by cAMP and JAK/STAT6 pathways in arginase deficiency. Mol. Cell Biol. 22:4491–4498.

An eye on insulin for almost 50 years. The nature of the growth promoting stimuli is not 1 1 well understood, but in ROP the Sarah K. Bronson, Chad E.N. Reiter, stimulus is assumed to be in part due and Thomas W. Gardner1,2 to perinatal retinal hyperoxia fol- lowed by hypoxia. The classic re- 1 Department of Cellular and Molecular Physiology, and sponse to hypoxia includes hypoxia- 2 Department of Ophthalmology, Penn State College of Medicine, Hershey, inducing factor-1 (HIF-1) translocation Pennsylvania, USA to the nucleus and subsequent Diabetic retinopathy, the most frequent complication of diabetes and downstream events such as the leading cause of vision loss, involves vascular and neural damage in the upregulation of VEGF, eNOS, and retina. Insulin and IGF-1 signaling are now shown (see the related arti- endothelin-1 (ET-1). The fact that cle beginning on page 1835) to contribute to retinal neovascularization, VEGF is increased in the vitreous of in part, by modulating the expression of various vascular mediators. diabetic patients makes it tempting to speculate that diabetes induces a J. Clin. Invest. 111:1817–1819 (2003). doi:10.1172/JCI200318927. hypoxic, or HIF-1–driven response that is similar to that observed in Physiologic and pathologic blood ves- tion, or perhaps stimulate appropri- ROP. Current animal models of dia- sel growth patterns are stimulated by ate vessel growth, to reduce maladap- betes do not develop proliferative local and systemic influences. The tive consequences. In the retina, nor- retinopathy and the only model that hope of angiogenesis research is to mal vessel growth occurs in the plane simulates the neovascularization understand these complex interac- of the retina from the optic nerve seen clinically is that induced by rel- tions in order to provide better means toward the periphery in a radial pat- ative hypoxia in developing retinas. to control pathologic vessel forma- tern and is guided by cues from astro- Postnatal mice are placed in hyper- cytes in the inner retina (1). This oxic conditions for several days, at a Address correspondence to: Thomas W. growth is mediated by VEGF and time when their vessels have not yet Gardner, Department of Cellular and other ligands (2), while angioblasts reached the peripheral retina, which Molecular Physiology, and Department of Ophthalmology, Penn State College of from the circulation can provide causes vasoconstriction; when they Medicine, 500 University Drive, Hershey, endothelial progenitors (3). are returned to room air, the vaso- Pennsylvania 17033, USA. constriction is relieved and neovas- Phone: (717) 531-6711; The problem of retinal cularization develops when the reti- Fax: (717) 531-7667; E-mail: [email protected]. neovascularization na perceives relative hypoxia (4). This Conflict of interest: The authors have Pathologic neovascularization of the model provides a rodent model of declared that no conflict of interest exists. retina is a common and serious com- neovascularization in the absence of Nonstandard abbreviations used: plication of retinopathy of prematu- systemic metabolic defects due to retinopathy of prematurity (ROP); diabetic retinopathy (DR); hypoxia-inducible factor-1 rity (ROP) and diabetic retinopathy insulin depletion or resistance. (HIF-1); endothelin-1 (ET-1); insulin receptor (DR). The treatment of DR, ablation Smith et al. (5) previously showed (IR); insulin-like growth factor-1 receptor of the diseased retina with laser pho- that an IGF-1 inhibitor blocked neo- (IGF-1R), vascular endothelial insulin tocoagulation or cryotherapy to cause vascularization in this model but no receptor knockout (VENIRKO); vascular endothelial insulin-like growth factor involution of the new vessels, has studies have examined the effect of receptor knockout (VENIFARKO). remained fundamentally unchanged the insulin receptor.

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