Immune modification due to chemical interference with transmembrane signalling: Application to polycyclic aromatic hydrocarbons

doi:10.1016/0192-0561(92)90167-J

International Journal of Immunopharmacology

Volume 14, Issue 3, April 1992, Pages 377-382

International Journa...

https://doi.org/10.1016/0192-0561(92)90167-J Get rights and content

Abstract

Triggering of the T-cell antigen receptor complex and some other surface molecules is coupled to the phosphodiesterase (phospholipase C)-mediated hydrolysis of membrane phosphoinositides, in particular, phosphatidylinositol-4,5-biphosphate (PiP2). PiP2 hydrolysis generates two products, inositol 1,4,5-triphosphate and diacylglycerol, which act in concert as second messengers to increase the free intracellular calcium concentration and activate protein kinase C, respectively, thereby stimulating subsequent events leading to cellular activation and proliferation. Transmembrane signalling in T-lymphocytes represents a potential target for designated drugs as well as immunotoxicants. Immunotoxic effects of polycyclic aromatic hydrocarbons are discussed in the view of interaction with transmembrane signalling in the T-lymphocyte.

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Differential scanning calorimetry (DSC) and electron paramagnetic resonance spectroscopy (EPR) experiments were performed on human erythrocyte membranes and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) model systems in order to study the effect the polycyclic aromatic hydrocarbons on lipid structure and dynamics. Eight different compounds among others naphthalene and pyrene were compared, which occur in significant concentrations in dust collected from the air in large cities.
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Previous studies have demonstrated that polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP) and 7,12-dimethybenz[a]anthracene (DMBA), and possibly 2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD), may exert their immunosuppressive effects by altering intracellular Ca²⁺homeostasis in lymphocytes. In these studies, we examined the effects of two immunosuppressive PAHs (BaP and DMBA), two nonimmunosuppressive PAHs (benzo[e]pyrene (BeP) and anthracene (ANTH)), and TCDD on intracellular Ca²⁺levels in surface marker-defined human peripheral blood mononuclear cells (HPBMC). BaP and DMBA, but not BeP and ANTH, were found to produce a time-dependent increase in intracellular Ca²⁺with maximal effects achieved following 42- to 66-hr exposures. In a series of studies with HPBMC obtained from 10 donors exposedin vitrofor 42 hr, BaP and DMBA were found to produce a significant increase in Ca²⁺in CD3⁺T cells, CD19⁺B cells, and CD14⁺monocytes. BeP and ANTH did not produce a statistically significant increase in Ca²⁺in the group of donors, but occasionally produced an apparent nonspecific elevation of Ca²⁺in HPBMC from individual donors. Interestingly, TCDD produced a small and statistically significant increase in Ca²⁺only in B cells analyzed for the pooled 10 donors. Certain BaP metabolites, such as the 7,8-dihydrodiol and the 7,8-diol-9,10-epoxide, were more effective in elevating Ca²⁺in HPBMC lymphocytes at 20 hr than was BaP. These results demonstrate in normal HPBMC that immunosuppressive PAHs alter intracellular Ca²⁺homeostasis in B cells, T cells, and monocytes, and suggest that P450 metabolism may play an important role in the immunotoxicity of certain PAHs.
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Immune modification due to chemical interference with transmembrane signalling: Application to polycyclic aromatic hydrocarbons

Abstract

Immun. Today

Adv. Immun.

Int. J. Immunopharmac.

J. biol. Chem.

Toxic. appl. Pharmac.

Intracellular calcium homeostasis

A. Rev. Biochem.

Corticosteroid-mediated immunoregulation in man

Immun. Rev.

Immunosuppression following 7,12-dimethylbenz(a)anthracene exposure in B6C3F1 mice II. — Altered cell-mediated immunity and tumoral resistance

Int. J. Immunopharmac.

Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation

Science

An analysis of the role of guanine nucleotide binding proteins in antigen receptor/CD3 antigen coupling to phospholipase C

J. Immun.

Suppression of murine cytotoxic T-lymphocyte induction following exposure to 7,12-dimethylbenz(a)anthracene: dysfunction of antigen recognition

Int. J. Immunopharmac.

Tumor promoters in conjunction with calcium ionophores mimic antigenic stimulation by reactivation of alloantigen-primed murine T lymphocytes

J. Immun.

Human T lymphocyte activation by tumor promoters: role of protein kinase C

J. Immun.

Immunosuppression following 7,12-dimethylbenz(a)anthracene exposure in B₆C₃F₁ mice II. — Altered cell-mediated immunity and tumoral resistance