A synergistic interaction of IL-6 and IL-1 mediates the thymocyte-stimulating activity produced by recombinant IL-1-stimulated fibroblasts.
We characterized the ability of normal human lung fibroblasts to elaborate thymocyte-stimulating activity, spontaneously, and in response to rIL-1. Supernatants from unstimulated fibroblasts did not contain thymocyte-stimulating activity, whereas supernatants from fibroblasts incubated with rIL-1 alpha or rIL-1 beta contained more thymocyte-stimulating activity than could be accounted for by passively transferred rIL-1 alone. This heightened thymocyte-stimulating activity was mediated by fibroblast-derived IL-6 inasmuch as it was neutralized by anti-serum against human rIL-6, and rIL-1-stimulated fibroblasts to accumulate messenger RNA for IL-6 and produce soluble IL-6 protein. However, IL-6 alone could not account for the intensity of this effect because rIL-6 only weakly stimulated thymocyte proliferation. In addition, antisera against the rIL-1 moiety that was used to prepare the supernatant had different effects on supernatants that contained and did not contain active IL-6. In the presence of IL-6 these antisera caused a greater decrease in thymocyte-stimulating activity than could be accounted for by passively transferred rIL-1 alone. When the IL-6 was neutralized the remaining thymocyte-stimulating activity could be quantitatively accounted for and neutralized by antisera against the rIL-1 that was passively transferred. Furthermore, rIL-6 and rIL-1 (alpha or beta) synergized in stimulating thymocyte proliferation. Thus, rIL-1 stimulates fibroblasts to produce a thymocyte-stimulating activity that is largely mediated by a synergistic interaction of fibroblast-derived IL-6 and IL-1. These findings suggest that fibroblast production of IL-6 may mediate or amplify some of the tissue effects of IL-1. In addition they suggest that biologic effects previously attributed to IL-1 may be due to IL-6 alone or the concerted action of IL-1 and IL-6.
Cardiovascular-Pulmonary Division, University of Pennsylvania School of Medicine, Philadelphia 19104.
J A
JA
Elias
G
G
Trinchieri
J M
JM
Beck
P L
PL
Simon
P B
PB
Sehgal
L T
LT
May
J A
JA
Kern
D000328:Adult; D001685:Biological Factors / Q000096:biosynthesis* / Q000502:physiology; D002474:Cell-Free System / Q000187:drug effects; D016207:Cytokines; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6; D007378:Interleukins / Q000494:pharmacology*; D008168:Lung; D008213:Lymphocyte Activation / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology*
D001685:Biological Factors; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D007378:Interleukins; D011994:Recombinant Proteins; C051922:thymocyte-activating factor, fibroblasts