Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor alpha and interferon in cancer patients

Wing, EJ; Magee, D. Mitchell; Tl, Whiteside; Kaplan, SS; Shadduck, RK

doi:10.1182/blood.v73.3.643.643

Cited by 160 publications

(17 citation statements)

References 11 publications

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“…3 Our data demonstrate that GM-CSF can augment the levels of activin A production from monocytes by more than 10-fold. GM-CSF also stimulates the production of many other cytokines in monocytes, including IL-1, TNF-a, G-CSF, M-CSF and IFN, [20][21][22][23] which, in turn, contribute to the inflammatory reactions and cell-mediated cytotoxicity of the effector cells. 3,22,23 In this context, it is intriguing that other pro-inflammatory cytokines, such as LPS and IFN-g, also stimulate the production of activin A in monocytes.…”

Section: Discussionmentioning

confidence: 99%

Induced expression of the new cytokine, activin A, in human monocytes: inhibition by glucocorticoids and retinoic acid

Shao

Frigon

et al. 1996

Immunology

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The capacity of recombinant human granulocyte–macrophage colony‐stimulating factor (GM‐CSF), glucocorticoids or all‐trans‐retinoic acid to modulate production of activin A by human monocytes was studied. It was shown that GM‐CSF stimulated monocytes to accumulate activin A RNA after as few as 4 hr of incubation, reaching a peak of stimulation at approximately 16 hr of incubation. The activin A transcripts accumulated in the monocytes after stimulation with only 5 U/ml of GM‐CSF and reached a maximum plateau level of expression between 25 and 50 U/ml of GM‐CSF. Biologically active activin A molecules were detected in the conditioned media by a bioassay, performed both in the absence and presence of a neutralizing antiserum for activin A. Accumulation of bioactive activin A in conditioned medium of monocyte cultures was detected after 24 hr of incubation with GM‐CSF and high levels of activin A were maintained for 72 hr. The production of the dimeric βAβA in these monocytes was further confirmed by a sandwich enzyme‐linked immunosorbent assay (ELISA) specific for activin A. In contrast to the stimulatory effect of GM‐CSF, hydrocortisone, dexamethasone or all‐trans‐retinoic acid at 1 × 10−7 to 1 × 10−5 m inhibited the constitutive expression of activin A and greatly suppressed the GM‐CSF‐stimulated production. Thus, the expression of activin A is modulated in monocytes by different agents. These observations may imply new roles for activin A at sites of inflammation where monocytes accumulate.

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Section: Discussionmentioning

confidence: 99%

Induced expression of the new cytokine, activin A, in human monocytes: inhibition by glucocorticoids and retinoic acid

Shao

Frigon

et al. 1996

Immunology

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“…Such stimulatory effects of IL-3 or GM-CSF on the production of IFN-a in vitro have not previously been described lo our knowledge. However, in vivo administration of GM-CSF enhances the IFN-a response in human monocytes when subsequently stimulated by lipopolysaccharide in vitro [19],…”

Section: Discussionmentioning

confidence: 99%

Interferons and the Colony‐Stimulating Factors IL‐3 and GM‐CSF Enhance the IFN‐α Response in Human Blood Leucocytes Induced by Herpes Simplex Virus

Cederblad

Alm

1991

Scand J Immunol

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Human peripheral blood mononuclear cells (PBMC) were stimulated to produce interferon-alpha (IFN-alpha) by glutaraldehyde-fixed Herpes simplex virus type 1 (HSV)-infected WISH amnion cells in vitro. Different cytokines were included during the stimulation and tested for their ability to enhance the IFN-alpha response which occurs in the natural IFN-alpha producing (NIP) leucocytes. The total production of IFN-alpha and the numbers of IFN-alpha producing cells (IPCs) were increased by interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Their most marked effect was to reduce the time required for induction of the IPC by the HSV-infected cells, thereby causing both an earlier peak of IPC numbers and secretion of IFN-alpha. Addition of IFN-alpha 2b did not alter the kinetics of the IFN-alpha response in the same way as the two CSFs, but instead generally increased the IPC numbers and the production of IFN-alpha. The IL-3 and GM-CSF, especially in combination with IFN-alpha, had the most pronounced enhancing effects on IPC numbers when PBMC were induced at low cell concentrations. The cytokines IL-1, IL-2, IL-4, IL-6 or tumour necrosis factor-alpha (TNF-alpha) had no detectable effects on the IFN-alpha response. The results suggest that cytokines such as the CSFs and IFNs may be involved in the regulation of NIP cell functions.

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“…Monocyte-mediated cytotoxicity depends on expression and biological activity of TNF. TNF may be secreted or exert tumouricidal activity following transmembrane expression (Philip & Epstein, 1986;Kriegler et al, 1988;Luettig et al, 1989;Wing et al, 1989;Peck et al, 1989Peck et al, , 1991Perez et al, 1990;Bernasconi et al, 1991;Woods & Chapes, 1993;van de Loosedrecht et al, 1993;Higuchi & Aggarwal, 1994). Transmembrane TNF mediates tumour cell apoptosis following direct contact of the effector cell and target cell (Cannistra et al, 1988;Kriegler et al, 1988;Perez et al, 1990;Bernasconi et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Administration of GM-CSF to human subjects increases monocyte TNF expression (Williams et al, 1995b). GM-CSF administration also increases monocyte TNF ADCC and killing of TNF-sensitive leukaemic cell-lines (Wing et al, 1989;Wiltchke et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Administration of GM-CSF to patients with refractory testicular cancer receiving myeloablative chemotherapy and autologous bone marrow transplantation augmented the production of TNF and monocyte-mediated cytotoxicity against the TNF sensitive U937 cell line (Wiltchke et al, 1995). In addition, the systemic administration of GM-CSF to patients with solid tumours resulted in an enhanced direct monocyte cytotoxicity against HT29 human colon carcinoma cells (Wing et al, 1989). GM-CSF administration also augments antibody dependent cellular cytotoxicity (ADCC) and TNF secretion of normal human monocytes in vivo (Nagler et al, 1996).…”

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confidence: 99%

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Monocyte‐mediated killing of human leukaemia is enhanced by administration of granulocyte‐macrophage colony stimulating factor following chemotherapy

1997

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Summary.We studied the capacity of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) to modulate monocyte anti-leukaemic activity when administered to patients following myelosuppressive chemotherapy. The leukaemic cell lines K562, U937 and KG-1 were used as models of human leukaemia as they exhibit differential sensitivity to cell-mediated or TNF-mediated cytotoxicity. Monocyte tumouricidal activity was augmented by rhGM-CSF or lipopolysaccharide (LPS) alone in vitro against leukaemic blasts, whereas granulocyte-colony stimulating factor (rhG-CSF) was without effect. rhGM-CSF and LPS exhibited an additive effect in stimulating the cytotoxic effect of monocytes against K562 blasts compared with either agent alone (P < 0 . 001). Both cell-mediated and soluble TNF-mediated killing of leukaemic blasts was augmented by rhGM-CSF administration to patients following chemotherapy. This effect persisted for up to 4 weeks after cessation of GM-CSF therapy. The administration of rhGM-CSF significantly increased the anti-leukaemic activity of monocytes against leukaemic targets that were resistant to secreted TNF, probably via a transmembrane TNFdependent mechanism. Therapy with rhG-CSF exhibited a minimal effect. We conclude that administration of rhGM-CSF, but not rhG-CSF, augments the tumouricidal properties of the monocyte-macrophage system, particularly during recovery from myelosuppressive chemotherapy. Moreover, the killing mechanism is direct and not mediated by an antibody-dependent cellular cytotoxic (ADCC) mechanism. Killing of TNF-resistant leukaemic cells in particular may be augmented via cell-to-cell contact.

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Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor alpha and interferon in cancer patients

Cited by 160 publications

References 11 publications

Induced expression of the new cytokine, activin A, in human monocytes: inhibition by glucocorticoids and retinoic acid

Induced expression of the new cytokine, activin A, in human monocytes: inhibition by glucocorticoids and retinoic acid

Interferons and the Colony‐Stimulating Factors IL‐3 and GM‐CSF Enhance the IFN‐α Response in Human Blood Leucocytes Induced by Herpes Simplex Virus

Monocyte‐mediated killing of human leukaemia is enhanced by administration of granulocyte‐macrophage colony stimulating factor following chemotherapy

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