Browsing by Author "Lupov, Ivan"

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    Acquired STAT4 deficiency as a consequence of cancer chemotherapy
    (2011-08-16) Lupov, Ivan; Chang, Hua-Chen; Randall, Stephen Karl, 1953-; Robertson, Michael J.
    Signal Transducer and Activator of Transcription 4 (STAT4) is an important transcription factor activated by IL-12 signaling. Activated STAT4 is essential for Th1 cell differentiation, a process characterized by increased potential for interferon (IFN)-γ production. Defective IFN-γ production due to STAT4 deficiency occurs after autologous stem cell transplantation for lymphoma. We have investigated the mechanisms of post-transplant STAT4 deficiency. The tumor-bearing state is ruled out to be the cause because STAT4 levels were not significantly different in peripheral blood mononuclear cells (PBMCs) obtained from lymphoma patients prior to treatment and healthy control subjects. The magnitude of the decrease in STAT4 levels corresponded with increasing intensity of chemotherapeutic treatment in vivo. Furthermore, treatment of normal PBMC cultures or a natural killer (NK) cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and reduced IL-12-induced IFN-γ production. Chemotherapy drugs are shown to have no impact on the stability of STAT4 mRNA, while steady-state levels of STAT4 transcripts are decreased in lymphoma patients. Our findings demonstrated that chemotherapeutic drugs up-regulate the ubiquitination rates of the STAT4 protein, which in turn promotes its degradation via the proteasome-mediated pathway. Treatment with the proteasome inhibitor bortezomib largely reversed the chemotherapy-induced STAT4 deficiency. Thus, acquired STAT4 deficiency in lymphoma patients is a consequence of treatment with chemotherapy. These results have important implications for design of optimal immunotherapy for lymphoma.
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    TYPE VI COLLAGEN STIMULATES MACROPHAGES TO PROMOTE INFLAMMATION
    (Office of the Vice Chancellor for Research, 2012-04-13) Voiles, Larry; Han, Ling; Lupov, Ivan; Chang, Hua-Chen
    Collagen VI (COL6), an extracellular matrix protein (ECM), is important in maintaining the integrity of the tissue. Our recent findings have demonstrat-ed that excess COL6 is present in the lungs of comorbid patients with em-physema and adenocarcinoma. COL6 localized in the pulmonary interstitium is likely to interact with endothelial, epithelial and infiltrated pulmonary mac-rophages. The hypothesis is that excessive COL6 activates macrophages to promote inflammation, which may exacerbate pulmonary diseases. To test our hypothesis, bone marrow derived macrophages or macrophage cell lines were stimulated with soluble COL6 followed by analysis of activation markers and pro inflammatory cytokines. And results showed an increase in the number of CD86 positive cells and the levels of IL-12 and IFNγ production following stimulation. Taken together, our data have provided a link between increased amounts of COL6 and subsequent immune responses, which may play a role in the pathogenesis of pulmonary inflammatory diseases.