Glutathione levels and depletion dramatically increase inflammatory response - explains one cause of variation in mold responses

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Glutathione levels in antigen-presenting cells modulate Th1 versus Th2

response patterns

http://www.pnas.org/content/95/6/3071.full

Current thinking attributes the balance between T helper 1 (Th1) and

Th2 cytokine response patterns in immune responses to the nature of

the antigen, the genetic composition of the host, and the cytokines

involved in the early interaction between T cells and

antigen-presenting cells. Here we introduce glutathione, a tripeptide

that regulates intracellular redox and other aspects of cell

physiology, as a key regulatory element in this process. By using

three different methods to deplete glutathione from T cell receptor

transgenic and conventional mice and studying in vivo and/or in vitro

responses to three distinct antigens, we show that glutathione levels

in antigen-presenting cells determine whether Th1 or Th2 response

patterns predominate. These findings present new insights into immune

response alterations in HIV and other diseases. Further, they

potentially offer an explanation for the well known differences in

immune responses in " Th1 " and " Th2 " mouse strains.

T helper 1 (Th1) and Th2 immune response patterns are defined both by

cytokine secretion and by immune functions (1–3). In general, the Th1

pattern is characterized by interleukin 12 (IL-12) and interferon γ

(IFN-γ) production and the up-regulation of cell-mediated, e.g.,

delayed hypersensitivity (DTH), responses (4, 5). The Th2 response

pattern is characterized by IL-4 and IL-10 production and the

up-regulation of a variety of antibody responses (2). Th1- and

Th2-associated cytokines tend to be reciprocally regulatory; IFN-γ

inhibits Th2-associated functions (6), and IL-4 and IL-10 inhibit

Th1-associated functions (7). In extreme cases, primary or secondary

immune responses may develop exclusively in either a Th1 or Th2

response pattern (6) and thus impair the body's overall ability to

combat infection (2, 8, 9).

Antigen-presenting cells (APC)—macrophages, dendritic cells, and B

cells—are central to the development of either Th1 or Th2 immunity

because antigen presentation and recognition are required to initiate

responses. Substantial evidence demonstrates that reciprocal cytokine

interactions involving APC regulate the balance between Th1 and Th2

response patterns, e.g., APC secrete IL-12, which drives IFN-γ

production, and the Th2-associated cytokine IL-10 (10) inhibits APC

IL-12 production and thereby drives IL-4 production (11). However, the

underlying mechanism(s) leading to the decision as to whether a Th1 or

Th2 cytokine pattern predominates in a given response are still not

clearly defined.

Studies presented here show that intracellular glutathione (GSH)

levels in APC influence the Th1/Th2 cytokine response pattern. GSH,

like nitric oxide (NO), is a small molecule that plays key roles in

basic metabolic and cell cycle-related processes. Among its many

functions, this cysteine-containing tripeptide reduces protein

disulfides, detoxifies free radicals and exogenous toxins, and

preserves the intracellular redox balance (12, 13). Previous studies

have shown that cyclophosphamide, x- or γ-irradiation, ethanol

consumption, and other agents alter immune responses (14–18) at

dosages known to deplete GSH (19–22). Here, we deplete GSH in vivo

and/or in vitro by treatment with three different agents (diethyl

maleate, ethanol, and cyclophosphamide) and examine in vivo and in

vitro responses to three well studied antigens (ovalbumin, fowl γ

globulin, and a synthetic copolymer of glutamic acid and tyrosine). We

show that in all cases, GSH depletion inhibits Th1-associated cytokine

production and/or favors Th2-associated responses. Further, by

charting the responses of isolated cell populations mixed in vitro, we

demonstrate clearly that the decrease in Th1 cytokine production is

due to the short-term, readily reversible depletion of APC GSH.