Steroids are not always immune suppressants.

[Guest guest]

I have been tied up elsewhere, and have not been able to respond to Cheryl

Re: Autoimmune Link In Juvenile Batten Disease, I have not forgotton but

need to put some time aside. I did think some here might find these interesting

so here they are..........

Jon.

--------------------------------------------------------------------------

Biochim Biophys Acta 1999 Oct 18;1472(1-2):222-31

The 7alpha-hydroxysteroids produced in human tonsils enhance the immune response

to tetanus toxoid and Bordetella pertussis antigens.

Lafaye P, Chmielewski V, Nato F, Mazie JC, Morfin R.

Departement des Biotechnologies, Institut Pasteur, Paris, France.

Human tonsils were assessed for their ability to 7alpha-hydroxylate pregnenolone

(PREG), dehydroepiandrosterone (DHEA) and 3-epiandrosterone (EPIA). Both

7alpha-hydroxy-DHEA and 7alpha-hydroxy-EPIA were produced by homogenates of

either whole tonsils or of lymphocyte-depleted tonsil fractions. In contrast,

isolated lymphocytes were found to be unable to carry out 7alpha-hydroxylation.

When co-cultures of tonsil-derived T and B lymphocytes were set up under

stimulatory conditions, IgGs were released in the supernatants and could be

quantitated, and immunomodulating properties of different steroids were

monitored. When PREG [7alpha-hydroxylate pregnenolone ] was added to a mixture

of tonsil-derived B and T lymphocytes, a decrease of non-specific and specific

IgG was observed. An increase in specific anti-tetanus toxoid and

anti-Bordetella pertussis antigen IgGs was obtained with either 1 microM

7alpha-hydroxy-DHEA or 1 microM 7alpha-hydroxy-EPIA. In contrast, DHEA and EPIA

were unable to trigger such an effect. When cultures of isolated tonsillar B

cells were used, none of the steroids tested showed significant effects on

specific IgG productions. These data led to the conclusion that human tonsillar

cells transform DHEA and EPIA, but not PREG, into 7alpha-hydroxylated

metabolites. These metabolites could act on target tonsillar T lymphocytes which

in turn act upon B lymphocytes for increasing specific IgG production.

PMID: 10572944 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

The plot thickens..........

Ann N Y Acad Sci 1998 May 1;840:317-27 , LinkOut

A positive role for thymus-derived steroids in formation of the T-cell

repertoire.

Vacchio MS, Ashwell JD, King LB.

Laboratory of Immunology, Food and Drug Administration, Bethesda, land

20852, USA. vacchio@...

T cells undergo rigorous selection processes in the thymus that are necessary to

prevent T cells with either autoreactive or nonfunctional T-cell receptors

(TCRs) from entering the periphery. Although both positive and negative

selection depend on TCR-mediated signals, the means by which a thymocyte

interprets these signals to result in survival or death is not understood.

Glucocorticoids are known to induce thymocyte apoptosis at high concentrations,

but at lower concentrations glucocorticoids can antagonize TCR-mediated

deletional signals and allow survival of thymocytes and T cell hybridomas.

Interestingly, transgenic mice in which the expression of the glucocorticoid

receptor has been downmodulated specifically in thymocytes have abnormal

thymocyte differentiation, indicating that glucocorticoids play a significant

role in T-cell development. Furthermore, we have demonstrated the presence of

steroidogenic enzymes in the thymic epithelium and can show that, in vitro,

these cells readily synthesize pregnenolone, the first product in the

steroidogenic pathway, and deoxycorticosterone. Inhibition of local

glucocorticoid biosynthesis in thymi from TCR transgenic mice during fetal

thymic organ culture (FTOC) revealed significant alterations in the process of

thymocyte selection. These data suggest that glucocorticoids do not simply

suppress the immune system but rather are necessary for thymocyte survival and

differentiation.

PMID: 9629259 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

J Exp Med 1994 Jun 1;179(6):1835-46

Steroid production in the thymus: implications for thymocyte selection.

Vacchio MS, Papadopoulos V, Ashwell JD.

Laboratory of Immune Cell Biology, National Cancer Institute, National

Institutes of Health, Bethesda, land 20892.

The mouse thymus was assessed for its ability to produce steroids. Cultured

thymic non-T cells produced soluble pregnenolone and deoxycorticosterone, and

immunohistochemistry demonstrated steroidogenic enzymes in radioresistant thymic

epithelial cells but not in thymocytes. Inhibition of thymic corticosterone

production or blockade of the glucocorticoid receptor with RU-486 resulted in

enhanced TCR-mediated, antigen-specific deletion of immature thymocytes. These

data indicate that locally produced glucocorticoids, because of their antagonism

of TCR-mediated signaling for death, may be a key element of antigen-specific

thymocyte selection.

PMID: 8195711 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

7 alpha-hydroxy-dehydroepiandrosterone and immune response.

Morfin R, Lafaye P, Cotillon AC, Nato F, Chmielewski V, Pompon D.

Laboratoire de Biotechnologie, Conservatoire National des Arts et Metiers, 2 rue

Conte, 75003 Paris, France. morfin@...

In human and murine lymphoid organs, circulating 3 beta-hydroxysteroids,

including pregnenolone (PREG), dehydroepiandrosterone (DHEA), and

epiandrosterone (EPIA), are 7 alpha-hydroxylated by a cytochrome P450 identified

in the hippocampus as P4507B1. Mouse and human lymphoid organs produced

different patterns of 3 beta-hydroxysteroid 7 alpha-hydroxylation with the

absence of pregnenolone and epiandrosterone hydroxylation in human and mouse,

respectively. Both 7 alpha-hydroxy-DHEA and 7 alpha-hydroxy-EPIA triggered a

significant increase of antitetanus toxoid and anti-Bordetella pertussis toxins

IgGs production in cultures of activated B + T cells derived from human tonsils,

whereas both 7 alpha-hydroxy-PREG and 7 alpha-hydroxy-DHEA increased the immune

response in mouse. Paracrine action of 7 alpha-hydroxysteroids resulted from

their production in cells of the lymphoid organs. Comparison of P4507B1

sequences in rat, human, and two mouse species showed that one amino acid change

might explain important differences in KM for 7 alpha-hydroxylation, and

suggested that such differences might contribute to the extent of immune

response.

Publication Types:

a.. Review

b.. Review, Tutorial

PMID: 11268429 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

Pregnenolone-7beta-hydroxylating activity of human cytochrome P450-1A1.

Doostzadeh J, Flinois JP, Beaune P, Morfin R.

Laboratoire de Biotechnologie, Conservatoire National des Arts et Metiers,

Paris, France.

In many human and murine tissues, both pregnenolone and dehydroepiandrosterone

are hydroxylated at the 7alpha and 7beta positions by a cytochrome

P450-containing microsomal complex. The 7alpha- and 7beta-hydroxysteroids

produced were shown to activate an immune response in mice. Based upon

identification by crystallization to constant specific activity and gas

chromatography-mass spectrometry analysis, we ascertained that a yeast-expressed

human cytochrome P450-1A1 was able to 7beta-hydroxylate pregnenolone (K(M) from

3.2 +/- 0.5 to 4.1 +/- 0.4 microM, turnover number from 117 +/- 15 to 135 +/- 13

pmol/min/nmol of cytochrome P450-1A1). The other human cytochromes P450 tested

did not produce identifiable quantities of 7alpha- or 7beta-hydroxylated

derivatives of pregnenolone or dehydroepiandrosterone. These findings indicate

that cytochrome P450-1A1 involvement in the 7beta-hydroxylation of pregnenolone

may contribute to the production of the 7-hydroxylated steroids necessary for

activation of the immune defences.