Potentiating effect of granulocyte-macrophage colony-stimulating factor on interleukin-1-induced thymocyte proliferation: evidence for an interleukin-2 and tumor necrosis factor-independent pathway.
The effect of Colony-Stimulating Factors (CSFs) on the growth of murine thymocytes was investigated. None among the following factors tested alone, i.e., Interleukin-3 (IL-3), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Granulocyte Colony-Stimulating Factor (G-CSF) or Macrophage Colony-Stimulating Factor (M-CSF) has been found to stimulate thymidine uptake by thymocytes. However, GM-CSF synergistically enhances thymocyte proliferation induced by Interleukin-1 (IL-1). Synergistic responses are obtained at a very pronounced level after 3 days of culture with very low factor concentrations (1.5 to 15 pM) and in the complete absence of mitogen. Similar effects are induced by IL-3, though to a lesser degree. In contrast, neither G-CSF nor M-CSF potentiate thymocyte proliferation promoted by IL-1. Kinetic studies show that the synergy between IL-1 and GM-CSF reaches its maximum after about 72 h of thymocyte culture and that it requires the simultaneous presence of both factors during the first 24 h. In addition, our data suggest that GM-CSF acts in synergy with IL-1 by an Interleukin-2 (IL-2)-independent pathway since: (i) incubation of thymocytes with GM-CSF in the presence of IL-1 does not significantly enhance the expression of the IL-2 receptors (IL-2R) as demonstrated by flow cytometry, and, (ii) specific monoclonal antibodies against murine IL-2 or IL-2R fail to reduce thymocyte proliferation in response to the synergistic combination. Similarly, the potentiating effect of GM-CSF on IL-1 thymocyte growth does not depend on Tumor Necrosis Factor alpha (TNF) since (i) the synergy for IL-1 and GM-CSF and that previously described for IL-1 and TNF cumulate and (ii) anti-TNF antibodies do not abolish the potentiating effect of GM-CSF.
INSERM U 25, CNRS UA 122, Hôpital Necker, Paris, France.
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Herbelin
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Machavoine
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Dy
D000818:Animals; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000502:physiology; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007375:Interleukin-1; D007376:Interleukin-2; D007377:Interleukin-3; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor