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European Journal of Immunology. 27(5):1213-20, 1997 May.

The induction of peripheral tolerance following oral antigen

administration in several autoimmune disease and conventional animal

models correlates with the production of transforming growth factor-beta

(TGF-beta) and T helper type 2 (Th2) cytokines. The factors regulating

TGF-beta production and its relation to the Th2 response, however, have

not been defined. We demonstrate that the systemic administration of

antibodies to interleukin (IL)-12 to ovalbumin (OVA)-T cell receptor (TCR)

transgenic mice fed high doses of OVA, followed by systemic OVA challenge,

substantially enhances TGF-beta, but not IL-4 production by peripheral T

cells. Furthermore, we demonstrate in an in vitro T cell differentiation

model that naive (CD4+/Mel-14hi) OVA-TCR-T cells stimulated with

OVA-pulsed dendritic cells (DC) produce four- to fivefold higher amounts

of TGF-beta when cultured with anti-IL-12 or anti-interferon-gamma

(IFN-gamma). In this in vitro system, IL-4 was not required for TGF-beta

production by T cells; however, it appeared to enhance levels of TGF-beta

by promoting the growth of TGF-beta-producing cells. Our findings

demonstrate that IL-12 and IFN-gamma are important negative regulators of

TGF-beta production both in vivo and in vitro, and that their modulation

may be of benefit for the treatment of autoimmune disorders.

Stern AS. Magram J. Presky DH.


Hoffmann-La Roche Inc. Nutley, NJ 07110-1199, USA.


Interleukin-12 an integral cytokine in the immune response. [Review] [147



Life Sciences. 58(8):639-54, 1996.

Interleukin 12 (IL-12) is a heterodimeric cytokine that is produced

primarily by antigen-presenting cells and plays a primary role in the

induction of cell-mediated immunity. This function is promoted by the

IL-12 induced production of interferon-gamma (IFN-gamma) from both resting

and activated NK and T cells, by the proliferative activity of IL-12 on

activated NK and T cells, by enhancing the cytotoxic activity of NK cells,

and by supporting cytotoxic T lymphocyte generation. IL-12 and

IL-12-induced IFN-gamma promote the development of naive T cells into Th1

cells and the proliferation and IFN-gamma secretion by differentiated Th1

cells in response to antigen. IL-12 has been found to exhibit many of

these activities in vivo, as well as in vitro, and thus IL-12 plays an

important role in both innate resistance and antigen-specific adaptive

immunity to intracellular bacterial, fungal, and protozoan pathogens. Due

to its effects on T cells, recombinant IL-12 has been shown to have

therapeutic activity in a variety of mouse tumor and infectious disease

models and is being evaluated in clinical trials in human cancer patients.

IL-12 also appears to play a role in the genesis of some forms of

immunopathology, including endotoxin-induced shock and some autoimmune

diseases associated with aberrant Th1 activity. Therefore, IL-12

antagonists may also have therapeutic potential in the treatment of auto

immune disorders. [References: 147]

Li C. Goodrich JM. Yang X.

Interferon-gamma (IFN-gamma) regulates production of IL-10 and IL-12 in

human herpesvirus-6 (HHV-6)-infected monocyte/macrophage lineage.

Clinical & Experimental Immunology. 109(3):421-5, 1997 Sep.

To determine whether HHV-6 infection induces expression and production of

IL-10 and IL-12 in monocytes/macrophages, and to explore the influence of

IFN-gamma on cytokine production in HHV-6-infected cells, expression and

production of IL-10 and IL-12 were evaluated through reverse

transcription-polymerase chain reaction (RT-PCR) and sandwich ELISA. HHV-6

infection induced the expression and the production of IL-10 and IL-12 in

monocytes and THP-1 cells. Kinetic study showed that the expression of

IL-12 mRNA decreased with accumulation of IL-10 mRNA. Expression and

production of IL-12 were markedly increased when anti-human IL-10 MoAbs

were added to the cultures, implying that endogenous IL-10 induced by

HHV-6 inhibited IL-12 production. Addition of increasing concentrations of

IFN-gamma to the cultures of HHV-6-infected cells enhanced the expression

of IL-12 gene, while the accumulation of IL-10 mRNA was down-regulated.

Determination of protein levels of IL-10 and IL-12 by ELISA also showed

that IFN-gamma increased IL-12 and decreased IL-10 production. These

results suggest that IFN-gamma regulates the production of IL-10 and IL-12

at transcriptional level mainly through inhibiting endogenous IL-10

production in HHV-6-infected monocyte/macrophage lineage.

Mielcarek M. Graf L. Johnson G. Torok-Storb B.

Production of interleukin-10 by granulocyte colony-stimulating

factor-mobilized blood products: a mechanism for monocyte-mediated

suppression of T-cell proliferation.

Blood. 92(1):215-22, 1998 Jul 1.

Previous reports showed that granulocyte colony-stimulating factor

(G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMC) are

hyporesponsive to alloantigen compared with control PBMC. In the current

study, _neutralizing antibodies to interleukin-10 (IL-10) . increased the

proliferative response of G-PBMC to alloantigen by 50. 14% (+/- 12.79%; n

= 8), whereas the proliferative response of control PBMC was not affected.

The inhibition of OKT3-stimulated CD4 cell proliferation by G-PBMC-derived

CD14(+) cells could also be abrogated by the addition of IL-10

neutralizing antibodies. Further, IL-10 levels correlated with the number

of CD14 cells in these cultures. Constitutive IL-10 mRNA levels detected

by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR)

were 10-fold higher in G-PBMC compared with control PBMC. This translated

into significantly higher IL-10 levels after 24-hour lipopolysaccharide

(LPS) stimulation of G-PBMC compared with control PBMC (P = .036). IL-10

mRNA levels were also fivefold higher in isolated G-PBMC-derived CD14

cells compared with control CD14 cells. This corresponded to increased

constitutive production of IL-10 by isolated G-PBMC-derived CD14 cells

compared with control CD14 cells (357.2 +/- 104.5 v 51.7 +/- 30.5, P =

.051). In conclusion, these data suggest that monocytes contained within

G-PBMC, which, in comparison to marrow, are increased in absolute number

and relative proportion to T cells, may suppress T-cell responsiveness by

secretion of IL-10.

Rohde T. MacLean DA. Richter EA. Kiens B. Pedersen BK.

Prolonged submaximal eccentric exercise is associated with increased

levels of plasma IL-6.

American Journal of Physiology. 273(1 Pt 1):E85-91, 1997 Jul.

To study the relationship between exercise-related muscle proteolysis and

the cytokine response, a prolonged eccentric exercise model of one leg was

used. Subjects performed two trials [a branched-chain amino acid (BCAA)

supplementation and a control trial]. The release of amino acids from

muscle during and after the eccentric exercise was decreased in the BCAA

trial, suggesting a suppression of net muscle protein degradation. The

plasma concentrations of interleukin (IL)-6 increased from 0.75 +/- 0.19

(preexercise) to 5.02 +/- 0.96 pg/ml (2 h postexercise) in the control

trial and in the BCAA supplementation trial from 1.07 +/- 0.41 to 4.15 +/-

1.21 pg/ml. Eccentric exercise had no effect on the concentrations of

neutrophils, lymphocytes, CD16+/CD56+, CD4+, CD8+, CD14+/CD38+, lymphocyte

proliferative response, or cytotoxic activities. BCAA supplementation

reduced the concentration of CD14+/CD38+ cells. This study shows that the

concentration of IL-6 in plasma is increased after prolonged eccentric

exercise and suggests that the cytokine response is independent of the

muscle proteolysis that occur during exercise.

Venkatraman JT. Pendergast D.

Effects of the level of dietary fat intake and endurance exercise on

plasma cytokines in runners.

Medicine & Science in Sports & Exercise. 30(8):1198-204, 1998 Aug.

PURPOSE:Chronic exercise and high fat diets have been associated with

immune suppression. We have reported the effects of level of dietary fat

and exercise on lymphocyte subsets, proliferative response, and in vitro

production of cytokines by peripheral blood mononuclear cells of runners.

The present study was planned to further investigate whether the

mechanisms of action of dietary fats is through their modulation of plasma

cytokines in runners. METHODS: This study compared plasma cytokines at

rest and after endurance exercise at 80% of V02max in female (N = 8-10)

and male (N = 8-10) runners after eating diets comprised of 17% (LF), 32%

(MF), and 41% (HF) fats (4 wk each). RESULTS: The level of interleukin-1

beta (IL-1 beta) was independent of gender, exercise, and level of dietary

fat. tumor necrosis factor (TNF-alpha) level was higher in the plasma of

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