Natural killer (NK) cell-derived hematopoietic colony-inhibiting activity and NK cytotoxic factor. Relationship with tumor necrosis factor and synergism with immune interferon.

Abstract

We characterize the natural killer (NK) cell colony-inhibiting activity (CIA) produced in supernatants from cultures of human peripheral blood lymphocytes (PBL) with NK-sensitive target cell lines, and study its relationship with NK cell-derived cytotoxic factor (NKCF). Using monoclonal antibodies (mAb) specific for NK cells or other lymphocyte populations, we unambiguously identify NK cells as the only PBL subset able to produce both NKCF and NK-CIA. We present functional and biochemical data suggesting that NKCF and NK-CIA represent the same molecule: (a) a highly significant positive correlation exists between the quantity of NKCF and NK-CIA in supernatants independently produced by different PBL subsets; (b) both NK-CIA and NKCF are induced by culture of PBL with NK-sensitive, but not with NK-insensitive cell lines, and with HLA-DR+ bone marrow cells; (c) both NKCF and NK-CIA are absorbed on the same cell lines or bone marrow cell types; (d) the two activities coelute in the same gel filtration fractions; (e) D-mannose-6-phosphate blocks both NKCF and NK-CIA activity, and prevents their absorption by K562 cells; and (f) both NKCF and NK-CIA activity are lost after 2 d at 37 degrees C. The NK-CIA-containing preparations are devoid of antiviral activity, and antiinterferon (anti-IFN) antibodies do not block the inhibitor activity of NK-CIA. The effect of NK-CIA on day 14 (early) colony-forming units of granulocytes and macrophages (CFU-GM) is synergistic with that of IFN-gamma, and this synergy is also evident on day 7 (late) CFU-GM growth. A combination of NK-CIA and IFN-gamma suppresses late CFU-GM, at concentrations of the two lymphokines that are completely ineffective when used independently. No synergy between NK-CIA and IFN-alpha or -beta was observed, due to a direct inhibitory effect of these two IFN types on late CFU-GM. Antibodies specific for tumor necrosis factor (TNF), but not those specific for lymphotoxins, inhibit both NK-CIA and NKCF activity in the NK cell-derived supernatant. Recombinant TNF, in the range of concentrations corresponding to that of the cytotoxic activity on L-929 cells present in supernatants, mediated both NKCF and NK-CIA activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Tumor necrosis factor-alpha inhibits stem cell factor-induced proliferation of human bone marrow progenitor cells in vitro. Role of p55 and p75 tumor necrosis factor receptors.

“…Similarly, after 1,6, and 24 h of treatment, TGF-,B1 (20 ng/ml) reduced the fraction of c-kit-positive cells to 37±2 (NS), 31±3 (P = 0.09), and 27±4% (P < 0.05), respectively ( Fig. 5).…”

“…TNF-a is a pleiotropic cytokine shown to act as both a positive and a negative regulator of myeloid cell proliferation and differentiation (1)(2)(3)(4)(5)(6)(7)(8)(9). The effects of TNF-a can be either directly mediated (7,10) or indirectly mediated by inducing other cells to produce hematopoietic growth factors (HGFs)' (11)(12)(13).…”

Cytokines and effector T cell subsets causing autoimmune CNS disease

“…IFN-c has a great impact on the regulation of the immune response [60] since many immune cells express the IFN-c receptor and respond to IFN-c: IFN-c stimulates the differentiation of Th1 cells, inhibits the differentiation of Th2 cells [61] and activates cytotoxic T cells and NK cells [62]. Furthermore IFN-c influences antibody production by promoting the secretion of IgG2a by B cells [63] and stimulates macrophages to produce tumor necrosis factor (TNF), IL-1, IL-6 and IL-8 [64].…”

Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells

“…In the mouse, interleukin-12 (IL-12)-induced interferon gamma (IFN-␥) production by mature NK cells 2,3 directs the development of Ag-specific cell-mediated responses to intracellular pathogens, controlling Th1 cell differentiation 4 (reviewed in Trinchieri and Scott 5 and Coffman et al 6 ). NK cells participate in the regulation of myeloid hematopoiesis, 7 and activation of myeloid 8 and monocytic cells (reviewed in Trinchieri et al 9 ) via production of granulocyte macrophage-colonystimulating factor (GM-CSF), IL-3, IFN-␥ and tumor necrosis factor alpha (TNF-␣). [10][11][12][13][14] They have also been proposed to participate in the regulation of humoral immune responses, 15,16 and to play a significant role in the asthma-associated eosinophilia 17,18 via IL-5 production, and possibly other factors.…”