Interleukin‐6 (IL‐6) induces either differentiation or growth of a variety of cells. Little is known about the molecular basis of this cellular decision. The family of signal transducer and activator of transcription (Stat) proteins are involved in signaling through a variety of cytokine and growth factor receptors, although their biological roles have not been established. To address whether Stat proteins play roles in IL‐6‐induced growth or differentiation, we introduced two types of mutant Stat3 acting in a dominant‐negative manner into M1 leukemic cells which respond to IL‐6 with growth arrest and terminal differentiation. We show that dominant‐negative forms of Stat3 inhibited both IL‐6‐induced growth arrest at G(0)/G1 and macrophage differentiation in the M1 transformants. Blocking of Stat activation resulted in inhibition of IL‐6‐induced repression of c‐myb and c‐myc. Furthermore, IL‐6 enhanced the growth of M1 cells primarily through shortening the length of the G1 period when Stat3 was suppressed. Thus IL‐6 generates both growth‐enhancing signals and growth arrest‐ and differentiation‐inducing signals at the same time. Stat3 may be a key molecule which determines the cellular decision from cell growth to differentiation in M1 cells.
Interleukin-6 (IL-6) activation of the immediate-early genejunB has been shown to require both a tyrosine kinase and an unknown 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7)-sensitive pathway. Here we report the identification and characterization of an IL-6 immediate-early response element in the junB promoter (designated JRE-HL6) in HepG2 cells. The JRE-IL6 element, located at -149 to -124, contains two DNA motifs, an Ets-binding site (EBS) (CAGGAAGC) and a CRE-like site (TGACGCGA). Functional studies using variously mutated JRE-IL6 elements showed that both motifs were necessary and sufficient for IL-6 response of the promoter. The EBS of the JRE-EL6 element (JEBS) appears to bind a protein in the Ets family or a related protein which could also form a major complex with the EBSs of the murine sarcoma virus long terminal repeat or human T-cell leukemia virus type 1 long terminal repeat. The CRE-like site appears to weakly bind multiple CREB-ATF family proteins. Despite the similarity in the structure between the JRE-IL6 element and the polyomavirus enhancer PyPEA3, composed of an EBS and an API-binding site and known to be activated by a variety of oncogene signals, JRE-IL6 could not be activated by activated Ha-Ras, Raf-1, or 12-O-tetradecanoylphorbol-13-acetate. We show that IL-6 activates JRE-HL6 through an H7-sensitive pathway that does not involve protein kinase C, cyclic AMP-dependent kinase, Ca2 -or calmodulin-dependent kinases, Ras, Raf-1, or NF-IL6 (C/EBPO). The combination of JEBS and the CRE-like site appears to form the basis for the selective and efficient response of JRE-IL6 to IL-6 signals, but not to signals generated by activated Ha-Ras, Raf-1, or protein kinase C.
Background: To assess the efficacy and to determine the risk factors of trabeculectomy with mitomycin C (MMC) in eyes with neovascular glaucoma (NVG) secondary to diabetic retinopathy. Methods: Kaplan-Meier survival analysis of the surgical outcome was performed on 35 eyes with NVG. Age, extent of peripheral anterior synechia, surgical history (cataract, glaucoma, vitrectomy), and concurrent retinal cryotherapy were evaluated to determine factors influencing the surgical outcome. The main criterion for success was a postoperative intraocular pressure (IOP) of ≤21 mm Hg. Results: The cumulative probability of success was 67.0% at 1 year and 61.8% after 2 to 3 years. The surgical outcome was significantly better in patients without a previous vitrectomy (p = 0.03). Extensive preoperative peripheral anterior synechia was also a risk factor for surgical failure (p = 0.013). Conclusions: Trabeculectomy with MMC can effectively reduce the elevated IOP associated with NVG. The extent of peripheral anterior synechia and a history of vitrectomy are significant negative predictors of surgical outcome.
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