Metallothionein differentially affects the host response to Listeria infection both with and without an additional stress from cold-restraint
Acute stress alters anti-bacterial defenses, but the neuroimmunological mechanisms underlying this association are not yet well understood. Metallothionein (MT), a cysteine-rich protein, is a stress response protein that is induced by a variety of chemical, biological, and psychological stressors, and MT has been shown to influence immune activities. We investigated MT’s role in the management of anti-bacterial responses that occur during stress, using a C57BL/6 (B6) strain that has targeted disruptions of the Mt1 and Mt2 genes (B6-MTKO), and a B6 strain that has additional copies of Mt (B6-MTTGN). The well-characterized listeriosis model was used to examine immune mechanisms that are altered by a 1-h stress treatment (cold-restraint, CR) administered just prior to bacterial infection. Intriguingly, MT gene doses both greater and lower than that of wild-type (WT) B6 mice were associated with improved host defenses against Listeria monocytogenes (LM). This augmented protection was diminished by CR stress in the MTKO mice, but transgenic mice with additional MT copies had no CR stress-induced increase in their listerial burden. During the transition from innate to adaptive immunity, on day 3 after infection, oxidative burst and apoptosis were assessed by flow cytometric methods, and cytokine transcription was measured by real-time quantitative PCR. MT gene expression and CR-stress affected the expression of IL-6 and TNFα. Additionally, these genetic and environmental modulations altered the generation of ROS responses as well as the number of apoptotic cells in livers and spleens. Although the level of MT altered the listerial response, MT expression was equally elevated by listerial infection with or without CR stress. These results indicate the ability of MT to regulate immune response mechanisms and demonstrate that increased amounts of MT can eliminate the immunosuppression induced by CR.
KeywordsMetallothionein Infection Listeria Apoptosis Oxidative stress
- Lynes MA, Richardson CA, McCabe R, Crowthers KC, Lee JC, Youn J, Schweitzer IB, Shultz LD (1999) In: MT IV Klaassen C (ed) Metallothionein-mediated changes in cell populations of autoimmune mice. Birkhauser Verlag, Basel, pp 437–444Google Scholar
- Lynes MA, Zaffuto K, Unfricht DW, Marusov G, Samson JS, Yin X (2006) The physiological roles of extracellular metallothionein. Exp Biol Med (Maywood) 231(9):1548–1554Google Scholar
- Raymond AD, Gekonge B, Giri MS, Hancock A, Papasavvas E, Chehimi J, Kossenkov AV, Nicols C, Yousef M, Mounzer K, Shull J, Kostman J, Showe L, Montaner LJ (2010) Increased metallothionein gene expression, zinc, and zinc-dependent resistance to apoptosis in circulating monocytes during HIV viremia. J Leukoc Biol 88(3):589–596PubMedCentralCrossRefPubMedGoogle Scholar
- Yang L, Wang J, Yang J, Schamber R, Hu N, Nair S, Xiong L, Ren J (2015) Antioxidant metallothionein alleviates endoplasmic reticulum stress-induced myocardial apoptosis and contractile dysfunction. Free Radic Res 12:1–33Google Scholar