Neutrophil chloramines: missing links between innate and acquired immunity

doi:10.1016/S0167-5699(97)01161-4

Immunology Today

Volume 18, Issue 12, December 1997, Pages 577-580

Immunology Today

https://doi.org/10.1016/S0167-5699(97)01161-4 Get rights and content

Abstract

Neutrophils are the major cellular component of the acute inflammatory response. By contrast, macrophages are the major cellular component in most chronic immunological responses, and act as key regulators of the specific acquired response. Here, Janusz Marcinkiewicz examines recent data indicating that chloramines, the neutrophil-specific products of the myeloperoxidase-hydrogen-peroxide-halide system, may provide a bridge between the afferent branches of the innate and acquired immune response.

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Citation Excerpt :
As discussed above, Met is an important source of the antioxidants glutathione and taurine (Pompella et al., 2003; Shimada et al., 2015). Taurine, which is the most abundant free AA in neutrophil cytosol, can act as a trap for hypochlorous acid, forming the long-lived, less reactive, and less toxic oxidant taurine monochloramine (Tau-Cl; Marcinkiewicz, 1997). Both in humans and mice, Tau-Cl had an anti-inflammatory effect by reducing cytokine production of stimulated neutrophils and monocytes (Marcinkiewicz et al., 1998; Chorazy et al., 2002).
Methionine, together with Lys, is the most limiting AA for milk production in dairy cows. Besides its crucial role in milk production, Met and its derivate metabolites (e.g., glutathione, taurine, polyamines) are well-known immunonutrients in nonruminants, helping support and boost immune function and activity. In the present study, the effects of Met or choline, as its precursor, were investigated using an ex vivo whole blood challenge. The study involved 33 multiparous Holstein cows (from a larger cohort with a factorial arrangement of treatments) assigned from d −21 to +30 relative to parturition to a basal control (CON) diet, CON plus rumen-protected Met (MET, Smartamine M, Adisseo NA, Alpharetta, GA) at a rate of 0.08% of dry matter, or CON plus rumen-protected choline (CHOL, ReaShure, Balchem Inc., New Hampton, NY) at 60 g/d. Blood was sampled on d −15, −7, 2, 7, and 20 for ex vivo lipopolysaccharide (LPS) challenge, and on d 1, 4, 14, and 28 relative to parturition for phagocytosis and oxidative burst assays. The MET cows had greater energy-corrected milk production and milk protein content. Overall, IL-6 response to LPS increased around parturition, whereas IL-1β remained constant, casting doubt on the existence of systemic immunosuppression in the peripartal period. Supplementation with MET dampened the postpartal blood response to LPS (lower IL-1β), while improving postpartum neutrophil and monocyte phagocytosis capacity and oxidative burst activity. In contrast, CHOL supplementation increased monocyte phagocytosis capacity. Overall, the data revealed a peripartal immune hyper-response, which appeared to have been mitigated by MET supplementation. Both MET and CHOL effectively improved immune function; however, MET affected the immune and antioxidant status before parturition, which might have been beneficial to prepare the cow to respond to metabolic challenges after parturition. These results provide insights on potential differences in the immunomodulatory action of methionine and choline in dairy cows. As such, the effects observed could have implications for ration formulation and dietary strategies.
Potential carcinogenic hazards of non-regulated disinfection by-products: Haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines
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Citation Excerpt :
This suggests that chloramination of both nitrogens might lead to bifunctional interactions with macromolecules, perhaps resulting from the formation of crosslinks (i.e. DNA to protein, protein to protein, or DNA with DNA). Organic N-chloramines have received attention in the biomedical literature as (1) mediators of inflammatory and anti-inflammatory effects that result from activation of neutrophils (Bernofsky, 1991; Davies et al., 1993; Marcinkiewicz, 1997; Barua et al., 2001; Vissers et al., 2001; Englert and Shacter, 2002; Kawai et al., 2004; Midwinter et al., 2004; Schuller-Levis and Park, 2004) and (2) they have been invoked as reactive metabolites produced by neutrophils that could account for a variety of chronic side effects of certain drugs (Uetrecht and Zahid, 1991; Uetrecht et al., 1995; Miyamoto et al., 1997). These studies suggest that organic N-halamines are toxicologically active, but provide little information on which to base a risk assessment related to their occurrence in drinking water.
Drinking water disinfectants react with natural organic material (NOM) present in source waters used for drinking water to produce a wide variety of by-products. Several hundred disinfections by-products (DBPs) have been identified, but none have been identified with sufficient carcinogenic potency to account for the cancer risks projected from epidemiological studies. In a search for DBPs that might fill this risk gap, the present study projected reactions of chlorine and chloramine that could occur with substructures present in NOM to produce novel by-products. A review of toxicological data on related compounds, supplemented by use of a quantitative structure toxicity relationship (QSTR) program TOPKAT^® identified chemicals with a high probability of being chronically toxic and/or carcinogenic among 489 established and novel DBPs. Classes of DBPs that were specifically examined were haloquinones (HQs), related halo-cyclopentene and cyclohexene (HCP&H) derivatives, halonitriles (HNs), organic N-chloramines (NCls), haloacetamides (HAMs), and nitrosamines (NAs). A review of toxicological data available for quinones suggested that HQs and HCP&H derivatives appeared likely to be of health concern and were predicted to have chronic lowest observed adverse effect levels (LOAELs) in the low μg/kg day range. Several HQs were predicted to be carcinogenic. Some have now been identified in drinking water. The broader class of HNs was explored by considering current toxicological data on haloacetonitriles and extending this to halopropionitriles. 2,2-dichloropropionitrile has been identified in drinking water at low concentrations, as well as the more widely recognized haloacetonitriles. The occurrence of HAMs has been previously documented. The very limited toxicological data on HAMs suggests that this class would have toxicological potencies similar to the dihaloacetic acids. Organic N-halamines are also known to be produced in drinking water treatment and have biological properties of concern, but no member has ever been characterized toxicologically beyond bacterial or in vitro studies of genotoxicity. The documented formation of several nitrosamines from secondary amines from both natural and industrial sources prompted exploration of the formation of additional nitrosamines. N-diphenylnitrosamine was identified in drinking waters. Of more interest, however, was the formation of phenazine (and subsequently N-chorophenazine) in a competing reaction. These are the first heterocyclic amines that have been identified as chlorination by-products. Consideration of the amounts detected of members of these by-product classes and their probable toxicological potency suggest a prioritization for obtaining more detailed toxicological data of HQs > HCP&H derivatives > NCls > HNs. Based upon a ubiquitous occurrence and virtual lack of in vivo toxicological data, NCls are the most difficult group to assign a priority as potential carcinogenic risks. This analysis indicates that research on the general problem of DBPs requires a more systematic approach than has been pursued in the past. Utilization of predictive chemical tools to guide further research can help bring resolution to the DBP issue by identifying likely DBPs with high toxicological potency.
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^☆: This work forms part of a continuing collaboration between the auther and Dr. Clain, and was supported by a Visiting Fellowship to J.M. form the Wellcome Trust, and by the polish Committee of Scientific Research.

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ViewpointNeutrophil chloramines: missing links between innate and acquired immunity☆

Abstract

Immunol. Today

Immunol. Today

Int. J. Biochem.

Frec Radic. Biol. Med.

Biochim. Biophys. Acta

Int. J. Biochem.

Immunopharmacology

Immunol. Today

Immunol. Today

Science

Curr. Opin. Immunol.

J. Leukocyte Biol.

Crit. Rev. Biochem. Mol. Biol.

Przegl. Lek.

Curr. Opin Immunol.

Curr. Opin. Immunol.

Viewpoint
Neutrophil chloramines: missing links between innate and acquired immunity☆