AK-5 Tumor-Induced Expression of Interleukin-12: Role of IL-12 in NK-Mediated AK-5 Regression

Hegde, Shrikanth P.; Bright, John J.; Kausalya, S.; Khar, Ashok

doi:10.1006/cimm.1995.1075

Cited by 18 publications

(13 citation statements)

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“…Our earlier observations also demonstrated an important role for IL-12 [16], IFN-g [17] and tumour necrosis factor (TNF)-a [18] in the regression of AK-5 tumour in syngeneic hosts. We have also shown that NK cell activation involved the induction of iNOS expression and enhanced nitrite production.…”

Section: Introductionmentioning

confidence: 53%

Interleukin‐2‐Induced Nitric Oxide Synthase and Nuclear Factor‐κB Activity in Activated Natural Killer Cells and the Production of Interferon‐γ

Jyothi

Khar

2000

Scand J Immunol

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Jyothi MD, Khar A. Interleukin-2-Induced Nitric Oxide Synthase and Nuclear Factor-kB Activity in Activated NK Cells and the Production of Interferon-g. Scand J Immunol 2000;52:148±155We have previously shown that inducible nitric oxide synthase (iNOS) was up-regulated in natural killer (NK) cells when AK-5 tumour cells were transplanted subcutaneously into syngeneic Wistar rats. This study was designed to investigate the role of interleukin (IL)-2 during the induction of iNOS and to understand the subsequent events involved in NK cell activation. There was up-regulation of iNOS expression when nai È ve NK cells were cultured in the presence of recombinant IL-2. These NK cells produced a higher nitrite content and possessed cytotoxic activity against YAC-1 and AK-5 tumour cells. Induction of iNOS enhanced nuclear factor (NF)-kB binding activity in IL-2 activated NK cells, which was con®rmed using L-NAME, an NO synthesis inhibitor. Addition of L-NAME along with rIL-2 signi®cantly blocked NF-kB activity and also down-regulated the production of NO and the cytotoxic activity of NK cells. Furthermore, injection of anti-IL-2 antibody in subcutaneous tumour transplanted animals abrogated signi®cantly the expression of iNOS and NF-kB activity, leading to reduced NO production and cytotoxic activity of NK cells against YAC-1 and AK-5 cells. In addition, the expression of interferon (IFN)-g by NK cells was also inhibited in anti-IL-2 antibody injected animals compared with the control animals. Finally, there was enhanced tumour growth and delayed regression in anti-IL-2 injected animals compared with control animals.

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Section: Introductionmentioning

confidence: 53%

Interleukin‐2‐Induced Nitric Oxide Synthase and Nuclear Factor‐κB Activity in Activated Natural Killer Cells and the Production of Interferon‐γ

Jyothi

Khar

2000

Scand J Immunol

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“…Earlier unpublished results from our laboratory showed that passive immunization with the anti-AK-5 antibody does not protect the animals from i. Kausalya et al, 1995;Hedge et al, 1995). Taken together, these results suggest that the anti-AK-5 antibody is necessary but not sufficient to medi¬ ate the rejection of the AK-5 tumor.…”

Section: Discussionmentioning

confidence: 71%

Molecular Cloning and Characterization of a Tumor Rejection Antigen from Rat Histiocytoma, AK-5

Muralikrishna

Begum²,

Swamy³

et al. 1998

DNA and Cell Biology

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We have cloned and sequenced a tumor rejection antigen from a highly immunogenic rat histiocytoma, AK-5. Recombinant antigen induced an antibody response in syngeneic hosts, and the immunized animals showed significant resistance to AK-5 tumor challenge, where growth of the tumor was retarded. Autologous anti-AK-5 antibody, as well as the specific monoclonal antibodies raised against whole AK-5 cells, recognized the recombinant protein. Similarly, recombinant antigen was able to neutralize antitumor antibody in a complement-mediated lysis assay. Antibodies raised against the fusion protein recognized a 60-kDa protein from AK-5 cell extracts. A cDNA sequence analysis revealed significant homology with mouse thymus (81%), lymph node (83%), and human brain (71%) cDNAs; however, the function of these genes is not known. These observations suggest the recombinant protein to be a strong candidate for the tumor rejection antigen that is involved in the spontaneous regression of the AK-5 tumor in syngeneic hosts.

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“…Spontaneous regression of histiocytic tumor (AK-5) was found to be associated with endogenous production of IL-12. This may be responsible for maintaining the NK cells in an activated state, thus demonstrating an efficient mechansim for complete tumor regression [22]. It is now becoming clear that IL-12 acts as both a proinflammatory cytokine and an immunomodulator, thus bridging the innate and adaptive immunoresponses.…”

Section: Discussionmentioning

confidence: 99%

Effect of a Recombinant Lectin, <i>Viscum album</i> Agglutinin on the Secretion of Interleukin-12 in Cultured Human Peripheral Blood Mononuclear Cells and on NK-Cell-Mediated Cytotoxicity of Rat Splenocytes in vitro and in vivo

Hajtò

Hostanska

Weber³

et al. 1998

Nat Immun

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A plant lectin, Viscum album agglutinin-I (VAA-I) has been shown to increase the number and cytotoxic activity of natural killer (NK) cells in animal models, but the mechanisms underlying these effects are poorly understood. We investigated the effects of the recombinant form of this lectin (rVAA) on secretion of interleukin (IL)-12 and on NK-mediated cytotoxicity against K562 target cells in cultures of human peripheral blood mononuclear cells (PBMC) as well as against YAC-1 target cells in cultured rat spleen cells. In 24-hour cultures of PBMC, 10 ng/ml plant VAA-I and 50 ng/ml rVAA induced significant increases in the secretion of total IL-12. Its biologically active heterodimeric form, p70, was also significantly induced by rVAA. Preincubation of PBMC or splenocytes for 48 h with rVAA in concentrations ranging between 10 pg/ml and 100 pg/ml resulted in moderate enhancements of NK-mediated cytotoxicity. However, coincubation of a low dose of rVAA (100 pg/ml) together with IL-2 and IL-12 (60 U/ml and 2 U/ml, respectively) led to additive stimulation of NK activity. In in vivo experiments, rVAA showed an enhancing effect on NK activity with a bell-shaped curve of efficacy. Forty-eight hours after a single intravenous injection of its most effective doses, 0.5 and 1 ng/kg, into Wistar rats, the NK cytotoxicity of splenocytes against YAC-1 targets doubled, and the frequency of large granular lymphocytes in peripheral blood showed 2.1- and 3-fold increases as compared to control animals. Twenty-four hours following these low lectin doses, the number of large granular lymphocytes was also significantly elevated. After 48 h, 0.5 ng/kg rVAA induced a significant augmentation in the percentage of peripheral Mac-1+ mononuclear cells, including activated monocytes and NK cells. The present results suggest that rVAA augments the secretion of an active form of IL-12 and potentiates the cytokine-induced NK activation. These effects of rVAA may be related to its stimulatory effects on MHC-unrestricted cytotoxicity in vivo.

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AK-5 Tumor-Induced Expression of Interleukin-12: Role of IL-12 in NK-Mediated AK-5 Regression

Cited by 18 publications

References 0 publications

Interleukin‐2‐Induced Nitric Oxide Synthase and Nuclear Factor‐κB Activity in Activated Natural Killer Cells and the Production of Interferon‐γ

Interleukin‐2‐Induced Nitric Oxide Synthase and Nuclear Factor‐κB Activity in Activated Natural Killer Cells and the Production of Interferon‐γ

Molecular Cloning and Characterization of a Tumor Rejection Antigen from Rat Histiocytoma, AK-5

Effect of a Recombinant Lectin, <i>Viscum album</i> Agglutinin on the Secretion of Interleukin-12 in Cultured Human Peripheral Blood Mononuclear Cells and on NK-Cell-Mediated Cytotoxicity of Rat Splenocytes in vitro and in vivo

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