CSF-1 regulation of Il6 gene expression by murine macrophages: a pivotal role for GM-CSF

We test the hypothesis that the monocyte-macrophage colony-stimulating fact or (CSF-1 or M-CSF) plays a major role in the inflammatory responses of M p hi by acting as a priming agent that heightens their responsiveness to seco ndary stimulation by other mediators. We previously reported that CSF-1 ind uced peritoneal M phi (PM phi) to transcribe several genes including interl eukin-6 (Il6) and,granulocyte-macrophage colony-stimulating factor (Csfgm), It was reported that the 116 and Csfgm genes were individually regulated b y different pathways but it was not clear to what extent the two genes inte racted during M phi-mediated inflammatory responses, We now show that CSF-1 induces the release of bioactive GM-CSF from mouse resident PM phi. GM-CSF induces 116 gene expression and synergizes with CSF-1 to induce the releas e of large amounts of IL-6, PM phi from C57BL/6J-Csfgm(null) mice were show n to release minimal IL-6 in response to CSF-1 and to express a much reduce d response to the highly stimulatory combination of CSF-1 and Lipopolysacch aride (LPS). Exogenous recombinant GM-CSF restored the IL-6 response of GM- CSF null PM phi to a great extent but not completely, As controls, three ot her recombinant proteins were tested but of these only tumor necrosis facto r alpha (TNF-alpha) was shown to synergize with both CSF-1 and GM-CSF, Usin g PM phi from mice deficient in the expression of the Il6 gene, it was show n that they released two- to threefold more GM-CSF in response to CSF-1 tha n their control counterparts, However, an exogenous supply of recombinant I L-6 had no effect on GM-CSF release, The data indicate that the pathways re gulating 116 gene expression are under the control of a complex network of cytokine interactions involving at least CSF-1, GM-CSF, and TNF-alpha, with the added possibility that IL-6 may exert modulatory activity within this network.