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
Реферат опубликован: 11/04/2005 (17586 прочтено)