Activation Of STAT Signaling Pathway Research Articles

Polysaccharides of Brassica rapa L. attenuate tumor growth via shifting macrophages to M1-like phenotype.

Macrophages are the major tumor-infiltrating leukocytes, and tumor-associated macrophages (TAM) play a critical role in cancer-related inflammation since they show alternative polarization to M1 (tumor-inhibited macrophages) or M2 (tumor-promoted macrophages) phenotype. Brassica rapa L. (B. rapa) has been clinically proven to have anti-tumor and immunity-enhancing activity, and the polysaccharides of B. rapa (BRP) have been reported to have an immunoregulatory effect on macrophages. In this study, we focus on macrophage polarization to investigate the mechanism of anti-tumor response of BRP in vivo and in vitro. We found that BRP improved the expression of M1 markers, including iNOS, COX-2, HLA-DR, CD11b and M1-related cytokines. The expression of M2 markers Arg-1, CD206 and CD163 induced by IL-4 were inhibited by BRP treatment, resulting in the inhibition of tumor growth both in vivo and in co-culture experiments in vitro. The activation of STAT signaling pathway were significantly regulated by BRP, which are important signals in TAM polarization. Overall, the results indicated that BRP has anti-tumor effect through mediating macrophage polarization.

Interleukin 29 inhibits RANKL-induced osteoclastogenesis via activation of JNK and STAT, and inhibition of NF-κB and NFATc1

Interleukin (IL)-29 is known to modulate immune functions of monocytes or macrophages. In this study, we investigated the effect and its underlying mechanism of IL-29 on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis using murine macrophage cell line RAW264.7 cells and bone-marrow-derived monocyte/macrophage precursor cells (BMMs), and human peripheral blood mononuclear cells (PBMCs). In response to human recombinant IL-29, cell viability and apoptosis were assessed by Cell Counting Kit-8 and flow cytometry; the osteoclast formation and activity by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assay, respectively; the expression and activation of molecules that associated with osteoclastogenesis by real time-PCR, immunoblotting or immunofluorescent analysis. IL-28 receptor α (IL-28Rα), a specific receptor of IL-29 was expressed on RAW264.7 cells. Although IL-29 did not affect the viability and apoptosis of RAW264.7 cells, it inhibited multinucleated cells in the differentiation of osteoclastogenesis, the bone-resorbing activity of mature osteoclasts and osteoclastic specific genes expression including TRAP, cathepsin K (CTSK), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), C-Fos and matrix metallopeptidase 9 (MMP-9). This inhibitory effect of IL-29 was confirmed on BMMs and PBMCs and mediated via IL-28Rα through the activation of Stat1 and 3 and the suppression of nuclear factor kappa B (NF-κB) and NFATc1 nuclear translocation in RAW264.7 cells. In conclusion, IL-29 inhibited osteoclastogenesis via activation of STAT signaling pathway, prevention of NF-κB activation and NFATc1 translocation, and suppression of downstream osteoclastogenic genes expression.

The role of STAT transcription factors in apoptosis regulation of hypothalamic neurons in aging in HER-2/neu transgenic mice and wild-type FVB/N mice.

For the firsts time, the involvement of the STAT pathway in the regulation of neuronal apoptosis in physiological aging and in old mice overexpressing the HER-2/neu oncogene was studied. We showed that suppression of STAT3, STAT5, and STAT6 and overexpression of the proapoptotic factor STAT1, which provides p53-mediated apoptosis, are the causes for increasing the number of apoptotic neurons in physiological aging. HER-2 tyrosine kinase receptor overexpression promotes neuronal survival through activation of STAT-signaling pathway with simultaneous suppression of the proapoptotic factor STAT1.

Activation of STAT signaling pathways and induction of suppressors of cytokine signaling (SOCS) proteins in mammalian lens by growth factors.

This study was conducted to examine whether the effects of growth factors are mediated in the lens by Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways and whether they induce expression of suppressors of cytokine signaling (SOCS), a novel family of feedback regulators of cytokine and growth factor activities. STAT activation and SOCS expression were analyzed in transgenic or wild-type mouse lens and lens epithelial cells stimulated with growth factors by immunohistochemistry, RT-PCR, Northern, Western, proliferation, or transient reporter assays. STATs were constitutively expressed at low levels and activated by insulin-like growth factor (IGF)-1, platelet-derived growth factor (PDGF)-aa, and FGF-1 or -2 in the lens. The Intensity of STAT signaling increased at high FGF-2 concentration and FGFs act in synergy with IGF-1 or PDGFaa to enhance STAT signaling and SOCS expression. Growth factor-induced proliferation of lens cells is inhibited by AG-490, a specific inhibitor of JAK2/STAT3. This is the first report that FGFs activate STAT pathways in the lens and that SOCS proteins are constitutively expressed and upregulated by growth factors in this tissue. Physiological relevance of STAT pathways in the lens is underscored by inhibition of lens cell proliferation by inhibitors of JAK/STAT pathways and by the aberrant proliferation of lens epithelium in the posterior pole of transgenic mice with constitutively activated STAT1 in the lens. Common activation of STAT pathways by FGF-1, FGF-2, IGF-1, or PDGFaa and their synergistic activation of STATs and SOCS in lens cells suggest that activities and crosstalk between these factors are sensitive to the steady state levels of activated STATs in the lens and may be under feedback regulation by SOCS family proteins.

Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line. Role of STAT pathway.

We recently described the expression of leukemia inhibitory factor (LIF) in human fetal and murine corticotrophs. LIF and the related cytokine oncostatin M induced basal, and corticotropin-releasing hormone (CRH) induced proopiomelanocortin (POMC) mRNA and ACTH secretion in AtT20 cells. LIF signaling and regulation of POMC gene transcription were therefore tested. Dexamethasone inhibited both basal- and LIF-induced ACTH secretion (P<0.05) and LIF induction of ACTH was also attenuated by immuneutralization of either the LIF receptor (35%, P<0.05) or the gp130 affinity converter (41%, P<0.05). These antisera also attenuated basal ACTH secretion in the absence of added ligand (P<0.05). To examine intrapituitary LIF signaling, phosphorylation of post-receptor substrates was measured. 1 nM LIF rapidly induced tyrosyl phosphorylation of STAT 1 and STAT 3 proteins, as well as tyrosyl phosphorylation of a 115-kD protein, coimmunoprecipitated with STAT 1. The transfected rat POMC promoter -706/+64, fused to the luciferase reporter gene, was induced by LIF, which exerted strong (18-fold) synergy with CRH. Deletion of the major CRH responsive region in POMC (-323/-166) abolished CRH induction of transcription and severely limited LIF synergy. Although 8 bromo cAMP or forskolin modestly enhanced POMC transcription (2.8-fold), LIF markedly potentiated (7.4-fold) these cAMP activators. These results demonstrate that corticotroph LIF action is receptor mediated and involves activation of STAT signaling pathways. LIF potently synergizes with both CRH and cAMP induction of POMC transcription. This novel intrapituitary signaling mechanism may mediate a neuroimmune pituitary interface.