IL-2 may be a limiting factor precluding lymphocytes from genetically resistant mice from responding to HgCl2

Jiang, Yun; Möller, Göran

doi:10.1093/intimm/11.5.627

Cited by 9 publications

(4 citation statements)

References 39 publications

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“…This suggests that low baseline levels of IL‐2, which are further reduced by exposure to Hg, play an important role in resistance to M‐HgIA in the A.TL strain. Indeed, Jiang and Möller [30] recently proposed that IL‐2 may be a limiting factor that prevents the lymphocytes in resistant DBA/2 mice from responding to Hg in vitro . Interestingly, it has been reported that self‐tolerance in mice is maintained by a CD25 + CD4 + subset of T‐cells that exert their suppressive effect by reducing expression of IL‐2 [31].…”

Section: Discussionmentioning

confidence: 99%

Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains

Häggqvist

Hultman

2001

Clinical and Experimental Immunology

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Cytokines play an important and complex role in the pathogenesis of systemic autoimmune diseases. In susceptible H‐2s mice, inorganic mercury (Hg) induces lymphoproliferation, antinucleolar antibodies against the 34‐kDa‐protein fibrillarin, and systemic immune‐complex (IC) deposits. Here, we report extensive analysis of cytokine mRNA levels in susceptible A.SW (H‐2s) and resistant A.TL (H‐2tl) mice under unstimulated conditions and during oral treatment with Hg and/or silver nitrate (Ag). Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay and phosphorimaging. Baseline expression of IL‐2 and IFN‐γ mRNA was higher in A.SW than in A.TL mice. In A.SW mice, Hg treatment caused early up‐regulation of IL‐2 and IFN‐γ levels, followed by substantial expression of IL‐4 mRNA, which was significant compared to control A.SW and Hg‐treated A.TL mice. Hg‐exposed A.TL mice exhibited unchanged IFN‐γ, reduced IL‐2 and greatly increased IL‐10 mRNA expression. Ag‐treated A.SW mice, which develop antifibrillarin antibodies (AFA) but exhibit minimal immune activation and no IC deposits, showed an early increase in IL‐2 and IFN‐γ mRNA, but only a small and delayed rise in IL‐4 mRNA. In conclusion, H‐2‐linked resistance to Hg‐induced AFA is characterized by low constitutive expression of IL‐2 and IFN‐γ mRNA, which is not increased by Hg, and a marked increase in IL‐10 expression. Conversely, the key features of H‐2‐linked susceptibility to Hg‐ and Ag‐induced AFA are up‐regulation of IL‐2, IFN‐γ and IL‐4 mRNA expression, and down‐regulation of IL‐10 expression.

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Section: Discussionmentioning

confidence: 99%

Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains

Häggqvist

Hultman

2001

Clinical and Experimental Immunology

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“…It has to be evaluated if the inability of the Vβ7+ T cells to respond directly to HgCl 2 is due to an inadequate ligation of the CD28 molecule. It has been proposed that IL–2 is a limiting factor for mouse splenic lymphocytes to respond to HgCl 2 , since even spleen cells from non–responder mouse strains could respond in the presence of exogenous IL–2: ‘IL–2 may be a limiting factor precluding lymphocytes from genetically resistant mice from responding to HgCl 2 ’ [52]. On the other hand, it has also been shown that mouse splenocytes pretreated with HgCl 2 for 1–3 days and analysed the day after washing had a much higher in vitro reactivity to HgCl 2 compared to cells continuously exposed to HgCl 2 [53].…”

Section: Discussionmentioning

confidence: 99%

HgCl<sub>2</sub>–Induced Human Lymphocyte Activation in vitro: A Superantigenic Mechanism?

Loftenius

Ekstrand²,

Möller³

1999

Int Arch Allergy Immunol

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Mercuric chloride (HgCl₂) has been proposed to be a mitogen for human blood lymphocytes in vitro. In our previous study, we demonstrated that HgCl₂ preferentially stimulates the CD4+ T cell subset to blast transformation and DNA synthesis and that the reaction is dependent on CD14+ accessory cells. In order to characterise the responding cells further and to elucidate the mechanism of T cell activation, the T cell receptor (TCR) Vβ chain expression of the blast–transformed cells was analysed by monoclonal antibodies and flow cytometry. The 22 TCR–Vβ–specific antibodies used were found to react with 55–80% of the naive CD4+ and CD8+ blood T cells from the different donors. Six to 18% of the lymphocytes, mainly CD4+ T cells, were blast transformed after addition of HgCl₂. The distribution of the lymphoblasts carrying certain TCR Vβ chains were skewed, and 15–40% expressed the TCR Vβ2 chain. Furthermore, if cells were pretreated for 5 days with HgCl₂, whereafter recombinant interleukin–2 in fresh medium was added, the TCR Vβ7+ T cell subset was also stimulated to blast transformation. The superantigen staphyloccal enterotoxin B, as a control, induced blast transformation in 10–26% of the lymphocytes, mainly CD4+ T cells, which were, as expected, positive for Vβ3, Vβ12, Vβ14 or Vβ17. We conclude that HgCl₂ has characteristics of a superantigen, activating the human lymphocytes in a Vβ–chain–selective manner in vitro.

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“…In rodents, HgCl 2 modulates T cells by induction of interleukins (IL) (e.g., IL-1 b ) and immunoglobulins (Ig) (e.g., IgG and IgE) (Griem et al, 1998), and by altering expression of costimulatory molecules (Roos et al, 1996); Hg stimulation of B lymphocytes may also mediate autoimmunity (Druet et al, 1982;Rose, 1993). In rodents, other features of Hg-induced autoimmune disease include generation of autoreactive CD4 + T cells (inhibition of Th1 and enhancement of Th2 subsets); synthesis of autoantibodies; glomerulonephritis; hypergammaglobulinemia; and regulation by IL-2 (Lawrence & McCabe, 1995;Kosuda et al, 1994Kosuda et al, , 1998Jiang & Moller, 1999;Abedi-Valugerdi et al, 1999). Interestingly, significant induction of serum concentrations of IgA, IgG, and IgM (compared to nonexposed healthy subjects) was observed in human workers exposed to Hg occupationally .…”

Section: Hg-induced Immunotoxicity In Mammalian Speciesmentioning

confidence: 99%

Toxicology and Immunotoxicology of Mercury: A Comparative Review in Fish and Humans

Sweet¹,

Zelikoff²

2001

Journal of Toxicology and Environmental Health Part B: Critical Reviews

206

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This review addresses an important area of environmental and mammalian toxicology by evaluating and comparing mercury-induced effects upon the immune responses of two evolutionarily divergent yet immunologically-related species. The mechanisms of mercury toxicology and immunotoxicology are described herein, including supporting data from the following: sources of exposure; bioavailability and biodistribution; metabolism; and laboratory and field investigations. Based upon the studies presented, the relative sensitivities of fish and human immune cells to mercury exposure are compared and contrasted with regard to mercury's ability to stimulate and/or suppress host immunocompetence. In addition, results from immune assays are compared to mercury tissue burdens, as well as to toxicological threshold level estimates. Such comparisons may help to resolve gaps in our knowledge regarding sensitivity of immunological assays, standardization of immunotoxicological techniques between species, and the extent to which the vertebrate immune system possesses functional reserve and redundancy in response to xenobiotics. A review of this type begins to provide support for the potential usefulness of fish immune cells to serve as indicators for human immunotoxicology risk assessment. Analysis of the reviewed studies supports the following conclusions in both lower and higher vertebrates: a threshold for mercury-induced immunotoxicological effects is likely; multiple exposure scenarios involving high and/or chronic exposures leading to increased body burdens are linked to increased risk of immunomodulation; and highly exposed and/or susceptible subpopulations are at greater risk of toxicological impact.

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IL-2 may be a limiting factor precluding lymphocytes from genetically resistant mice from responding to HgCl2

Cited by 9 publications

References 39 publications

Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains

Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains

HgCl<sub>2</sub>–Induced Human Lymphocyte Activation in vitro: A Superantigenic Mechanism?

Toxicology and Immunotoxicology of Mercury: A Comparative Review in Fish and Humans

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