Inflammatory Mediators are Inhibited by a Taurine Metabolite in CpG Oligodeoxynucleotide and IFN-r Activated Macrophage Cell Line

May 2013 | Volume 12 | Issue 5 | Original Article | 551 | Copyright © 2013

Bo Sook Kim DVM PhD,a Daryl S. Spinner PhD,b Richard J. Kascsak PhD,b Seung Yong Park DVM PhD,c In Soo Cho DVM PhD,d Georgia Schuller-Levis PhD,e and Eunkyue Park PhDe

aSeoul Grand Park Zoo,Gwacheon, Gyunggi-do, 427-702 Korea
cCollege of Veterinary Medicine, Konkuk University, Seoul, 143-701 Korea
dAnimal, Plant and Fisheries Quarantine and Inspection Agency, Anyang, Gyunggi-do, 430-757 Republic of Korea
bDepartment of Developmental Biochemistry and eDevelopmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY

Abstract

Taurine plays an important role in brain and retinal development, and has an antiinflammatory and antioxidant function. Taurine chloramine (Tau-Cl) is produced in polymorphonuclear leukocytes via the myeloperoxidase/halide system. We previously demonstrated that Tau-Cl inhibits the production of nitric oxide (NO) and TNF-α in human and murine macrophages activated with IFN-γ in combination with individual Toll-like receptor (TLR) ligands including those for TLR2 and/or TLR4. In the current study, we further explored the effects of Tau-Cl in RAW 264.7 cells stimulated with the TLR9 ligand CpG oligodeoxynucleotide (ODN). Specifically, we examined the effect of CpG ODN plus IFN-γ on the production of NO and TNF-α, and the effect of Tau-Cl on this process. Our findings show that CpG ODN plus IFN-γ-activated RAW 264.7 cells secrete high levels of NO and TNF-α, and that Tau-Cl (0.8 mM) inhibits this effect in a dose-dependent manner, more potently inhibiting the production of NO (99% inhibition) than that of TNF-α (48% inhibition). Nitric oxide synthase (iNOS) protein was also induced by CpG ODN plus IFN-γ, and was also inhibited by Tau-Cl. Furthermore, while CpG ODN plus IFN-γ induced TNF-α and iNOS mRNAs, Tau-Cl transiently suppressed this effect. Taurine itself had no effects on any of these processes. Our findings in a macrophage cell line demonstrate that Tau-Cl inhibits proinflammatory mediators resulting from TLR9 activation, and have implications for the utility of Tau-Cl in scenarios where such activation is deleterious such as in autoimmune conditions or infections in which overwhelming inflammation may occur. CpG ODNs and Tau-Cl both have potential for topical treatment of autoimmune conditions, including psoriasis, vitiligo, and alopecia areata. As CpG ODNs may, under some conditions, up-regulate Tregs, addition of Tau-Cl to CpG ODN topical formulations has potential for improving cancer immunotherapy.

J Drugs Dermatol. 2013;12(5):551-557.

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INTRODUCTION

Taurine is one of the most abundant amino acids in physiological fluids and tissues including serum, leukocytes, brain, kidney, and liver. Taurine is a ubiquitous single amino acid that is a conditional essential amino acid in humans and primates, as well as an essential amino acid for felines. Taurine is not incorporated into proteins but plays an important role in several biological processes such as the development of organ systems such as the central nervous system and retina, and physiological functions such as reproduction, calcium modulation, membrane stabilization, and immunity.1,2 Taurine protects tissues from damage caused by overt inflammatory responses in a variety of model systems.3-6 Although the mechanism(s) of protection by taurine is not well understood, much attention has focused on the ability of taurine to attenuate the indiscriminate cellular damage caused by HOCl/OCl- via the formation of Tau-Cl.7,8 The formation of Tau-Cl may also be catalyzed directly by the halide-dependent myeloperoxidase that is associated with PMNs, eosinophils, and basophils.9

The engagement of TLRs triggers a cascade of cell signaling events that culminate in leukocyte gene expression and the up-regulation of a variety of innate immune responses including production of proinflammatory cytokines.10-13 These innate immune responses control the spread of infection and direct the development of adaptive immune responses. There is remarkable redundancy built into this system as different TLR family members bind unique pathogen components, yet signal through a common NFkB signaling cascade to ensure an effective host immune response. Although TLR family members signal through a common signaling cascade, the consequence of TLR activation is dependent upon the specific TLR activated, the cell on which the TLR is activated, and the nature of the ligand. Microbial DNA serves as the physiological ligand for TLR9 which is one of the TLR family members, also including TLRs 3, 7, and 8, localized to the intracellular endosomal compartment, differing from membrane-bound TLRs.14-16 In nature, TLR activation is generally associated with infection and the induction of a Th1 milieu through secretion of key cytokines by a variety of cell types, including macrophages, dendritic cells, T cells and natural killer (NK) cells. The presence of IFN-g and other cytokines characteristic of a Th1 immune response, including IL-1 is indicative of a mature immune response, and induces heightened surveillance of macrophages to detect incoming pathogens.17,18

Over the course of evolution, the vertebrate immune system has developed the capacity to recognize subtle differences

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