Oppenheimer-Marks N.  Brezinschek RI.  Mohamadzadeh M.  Vita R.  Lipsky

  PE.

   _Interleukin 15 . is produced by endothelial cells and increases the

  transendothelial migration of T cells In vitro and in the SCID mouse-human

  rheumatoid arthritis model In vivo.

Source

  Journal of Clinical Investigation.  101(6):1261-72, 1998 Mar 15.

The capacity of endothelial cells (EC) to produce IL-15 and the capacity

  of IL-15 to influence transendothelial migration of T cells was examined.

  Human umbilical vein endothelial cells expressed both IL-15 mRNA and

  protein. Moreover, endothelial-derived IL-15 enhanced transendothelial

  migration of T cells as evidenced by the inhibition of this process by

  blocking monoclonal antibodies to IL-15. IL-15 enhanced transendothelial

  migration of T cells by activating the binding capacity of the integrin

  adhesion molecule LFA-1 (CD11a/CD18) and also increased T cell motility.

  In addition, IL-15 induced expression of the early activation molecule

  CD69. The importance of IL-15 in regulating migration of T cells in vivo

  was documented by its capacity to enhance accumulation of adoptively

  transferred human T cells in rheumatoid arthritis synovial tissue

  engrafted into immune deficient SCID mice. These results demonstrate that

  EC produce IL-15 and imply that endothelial IL-15 plays a critical role in

  stimulation of T cells to extravasate into inflammatory tissue.

  Lantero S.  Sacco O.  Scala C.  Rossi GA.

  Stimulation of blood mononuclear cells of atopic children with the

  relevant allergen induces the release of eosinophil chemotaxins such as

   _IL-3, IL-5, and GM-CSF.

  Journal of Asthma.  34(2):141-52, 1997.

Peripheral blood mononuclear cells (PBMC) from 10 atopic asthmatic

  children (atopics), sensitized to Dermatophagoides pteronyssinus (Dp), and

  from 5 nonatopic healthy children (controls) were stimulated with Dp

  extract or with birch extract (Be). After 6 days we tested the

  supernatant's (Sn) chemotactic activity toward purified blood

  eosinbnophils and T-lymphocyte proliferation. Dp induced a statistically

  significant T-cell proliferation from atopics as compared to controls (p <

  0.05), which correlated with the levels of eosinophil chemotactic activity

  in the Sn (r = 0.713; p < 0.05). Measurable levels of IL-3, IL-5, and

  GM-CSF were demonstrated in the Sn of Dp-stimulated PBMC from atopics,

  while eosinophil locomotion toward different concentrations of recombinant

  human (rh) IL-3, rhIL-5, and rhGM-CSF confirmed that these cytokines were

  able to stimulate eosinophil chemotaxis in a close concentration range.

  Preincubation of different concentrations of the same Sn with blocking

  antisera demonstrated that anti-human (ah) IL-3, ahIL-5, and ahGM-CSF

  effectively decreased eosinophil chemotaxis (p < 0.05; each comparison).

  Thus PBMC activation with the relevant allergen induces the release by T

  cells with a Th2 phenotype of chemotactic factors for eosinophils.

  Ogawa M.  Tsutsui T.  Zou JP.  Mu J.  Wijesuriya R.  Yu WG.  Herrmann S.

  Kubo T.  Fujiwara H.  Hamaoka T.

  Enhanced induction of very late antigen 4/lymphocyte function-associated

   _antigen 1-dependent T-cell migration to tumor sites following

   _administration of interleukin 12.

   Cancer Research.  57(11):2216-22, 1997 Jun 1.

Administration of interleukin 12 (IL-12) into mice bearing CSA1M, OV-HM,

  Meth A, or MCH-1-A1 tumor induced complete regression of CSA1M and OV-HM

  tumors but induced only a slight growth inhibition of Meth A and MCH-1-A1

  tumors. These effects of IL-12 were associated with high and only marginal

  levels of T-cell infiltration into CSA1M/OV-HM and Meth A/MCH-1-A1 tumor

  masses, respectively. Here, we investigated the role of IL-12 in the

  induction of T-cell migration. Spleen cells from untreated or

  IL-12-treated CSA1M-bearing mice were stained in vitro with a fluorescein

  chemical and transferred i.v. into IL-12-untreated CSA1M-bearing mice.

  Migration of donor cells was quantitated by counting the number of

  fluorescent cells on cryostat sections of tumor masses. Although only a

  slight migration was detected for spleen cells from IL-12-untreated

  CSA1M-bearing as well as IL-12-treated or untreated normal mice, enhanced

  migration was observed for cells from IL-12-treated CSA1M-bearing mice. A

  similar enhanced migration was observed for the OV-HM model. In contrast,

  such an enhancement was only marginal in the Meth A and MCH-1-A1 models.

  Immunohistochemical studies of tumors from IL-12-treated mice revealed

  that the predominant T-cell subset was CD4+ in CSA1M and CD8+ in OV-HM

  tumor masses. Consistent with this observation, the dominant subset of

  migrating T cells was found to be CD4+ in the CSA1M and CD8+ in the OV-HM

  models. T-cell migration was inhibited by pretreatment of recipients with

  either combination of anti-very late antigen 4 + anti-vascular cell

  adhesion molecule 1 or anti-lymphocyte function-associated antigen 1 +

  anti-intercellular adhesion molecule 1 monoclonal antibody. These results

  indicate that IL-12 can confer T cells with a capacity to migrate to tumor

  sites through very late antigen 4/lymphocyte function-associated antigen 1

  adhesion pathways and that the in vivo acquisition of such a capacity

  following IL-12 treatment correlates with the induction of tumor

  regression.

  Marth T.  Strober W.  Seder RA.  Kelsall BL.

  Regulation of transforming growth factor-beta production by

  interleukin-12.

Source

  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.

Institution

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

Title

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

  refs]

Source

  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

  men compared with that in women runners, and the level of these two

  cytokines increased with increasing level of dietary fat. Plasma

  interleukin-2 (IL-2) level (a cytokine involved in enhancing T cell

  functions for host defense) was significantly higher in men compared with

  that in women runners and decreased in men with increase dietary fat.

  Plasma interleukin-6(IL-6) level was significantly lower after the

  endurance run, and IL-6 levels decreased with increase in dietary fat.

  CONCLUSIONS: Data from the present study suggest that dietary fat has

  differential effects on plasma cytokine levels in runners. Increasing the

  level of dietary fat significantly increased endurance run time and had no

  adverse effects on the level of plasma IL-2 and pro-inflammatory cytokines

  (IL-1 beta, IL-6 and TNF-alpha in runners.