Subbarao Bondada

Publications (36) View all

• Article: Multifactorial patterns of gene expression in colonic epithelial cells predict disease phenotypes in experimental colitis.

  Aubrey L Frantz, Maria E C Bruno, Eric W Rogier, Halide Tuna, Donald A Cohen, Subbarao Bondada, R Lakshman Chelvarajan, J Anthony Brandon, C Darrell Jennings, Charlotte S Kaetzel
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  ABSTRACT: The pathogenesis of inflammatory bowel disease (IBD) is complex and the need to identify molecular biomarkers is critical. Epithelial cells play a central role in maintaining intestinal homeostasis. We previously identified five "signature" biomarkers in colonic epithelial cells (CEC) that are predictive of disease phenotype in Crohn's disease. Here we investigate the ability of CEC biomarkers to define the mechanism and severity of intestinal inflammation. We analyzed the expression of RelA, A20, pIgR, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-2 in CEC of mice with dextran sodium sulfate (DSS) acute colitis or T-cell-mediated chronic colitis. Factor analysis was used to combine the five biomarkers into two multifactorial principal components (PCs). PC scores for individual mice were correlated with disease severity. For both colitis models, PC1 was strongly weighted toward RelA, A20, and pIgR, and PC2 was strongly weighted toward TNF and MIP-2, while the contributions of other biomarkers varied depending on the etiology of inflammation. Disease severity was correlated with elevated PC2 scores in DSS colitis and reduced PC1 scores in T-cell transfer colitis. Downregulation of pIgR was a common feature observed in both colitis models and was associated with altered cellular localization of pIgR and failure to transport IgA. A multifactorial analysis of epithelial gene expression may be more informative than examining single gene responses in IBD. These results provide insight into the homeostatic and proinflammatory functions of CEC in IBD pathogenesis and suggest that biomarker analysis could be useful for evaluating therapeutic options for IBD patients. (Inflamm Bowel Dis 2012;).
  Inflammatory Bowel Diseases 11/2012; 18(11):2138-48. · 4.86 Impact Factor
• Article: Bone Marrow Dendritic Cell-Mediated Regulation of TLR and B Cell Receptor Signaling in B Cells.

  Vishal J Sindhava, Halide Tuna, Beth W Gachuki, David J Dilillo, Margarita G Avdiushko, Thandi M Onami, Thomas F Tedder, Donald A Cohen, Subbarao Bondada
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  ABSTRACT: Dendritic cells (DCs) play an essential role in regulation of immune responses. In the periphery, Ag presentation by DCs is critical for adaptive responses; for this reason, DCs are often targets of adjuvants that enhance vaccine responses. Activated mature DCs enhance B cell activation and differentiation by providing cytokines like BAFF and a proliferation-inducing ligand. However, the role of immature DCs in B cell tolerance is not well studied. Recently, mouse immature bone marrow-derived DCs (iBMDCs) have been shown to suppress anti-IgM-induced B cell activation. In this study, we tested the ability of mouse DCs to modulate B cell functions during TLR activation. We found that iBMDCs potently suppressed proliferation and differentiation of various B cell subsets on TLR stimulation. However, iBMDCs did not affect CD40-mediated B cell activation. Optimal suppression of B cell activation by iBMDCs required cell contact via the CD22 receptor on B cells. The B cell suppression was a property of iBMDCs or DCs resident in the bone marrow (BM), but not mature BM-derived DCs or DCs resident in the spleen. Presence of iBMDCs also enhanced the Ag-induced apoptotic response of BM B cells, suggesting that the suppressive effects of iBMDCs may have a role in B cell tolerance.
  The Journal of Immunology 08/2012; 189(7):3355-67. · 5.79 Impact Factor
• Article: Systemic Par-4 inhibits non-autochthonous tumor growth.

  Yanming Zhao, Ravshan Burikhanov, Jason Brandon, Shirley Qiu, Brent J Shelton, Brett Spear, Subbarao Bondada, Scott Bryson, Vivek M Rangnekar
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  ABSTRACT: The tumor suppressor protein Par-4 (Prostate apoptosis response-4) is spontaneously secreted by normal and cancer cells. Extracellular Par-4 induces caspase-dependent apoptosis in cancer cell cultures by binding, via its effector SAC domain, to cell surface GRP78 receptor. However, the functional significance of extracellular Par-4/SAC has not been validated in animal models. We show that Par-4/SAC-transgenic mice express systemic Par-4/SAC protein and are resistant to the growth of non-autochthonous tumors. Consistently, secretory Par-4/SAC pro-apoptotic activity can be transferred from these cancer-resistant transgenic mice to cancer-susceptible mice by bone marrow transplantation. Moreover, intravenous injection of recombinant Par-4 or SAC protein inhibits metastasis of cancer cells. Collectively, our findings indicate that extracellular Par-4/SAC is systemically functional in inhibition of tumor growth and metastasis progression, and may merit investigation as a therapy.
  Cancer biology & therapy 07/2011; 12(2):152-7. · 2.64 Impact Factor
• Article: Role of phosphoinositide 3-kinase-Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages stimulated via TLR-2 or TLR-4 receptors.

  Mosoka P Fallah, R Lakshman Chelvarajan, Beth A Garvy, Subbarao Bondada
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  ABSTRACT: Age-associated defects in both B-lymphocytes and macrophages in elderly result in a reduction in the efficacy of vaccines to many Gram positive bacteria like Streptococcus pneumoniae. Splenic macrophages from aged mice have been shown to have a defect in production of pro-inflammatory cytokines (IL-6, IL-12, IL-1β, TNF-α) but exhibit increased production of IL-10 upon TLR-4 ligation. Here we showed that aged macrophages demonstrate similar cytokine dysregulation phenotype upon stimulation with TLR-2 ligands, or killed S. pneumoniae. We hypothesized that an age-associated increase in activity of phosphatidyl inositol 3-kinase (PI3K)-Akt signaling pathway may be playing a causal role in the age-associated cytokine dysregulation. We found that gene expression of both the regulatory (p85β) and the catalytic (p110δ) subunits of Class IA PI3K is higher in aged than in young splenic macrophages. The age-associated increase in the activity of PI3K was also demonstrated by an upregulation of P-Akt and its downstream target, glycogen synthase kinase-3 (GSK-3). Inhibition of PI3K enhanced induction of pro-inflammatory cytokines, by TLR-2/TLR-1, TLR-2/TLR-6 and TLR-4 ligands as well as heat killed S. pneumoniae (HKSP). Therefore, targeting PI3-Kinase could rescue cytokine dysregulation in aged macrophages and enhance the relevant pro-inflammatory cytokines needed to support B-cell activation and differentiation.
  Mechanisms of ageing and development 05/2011; 132(6-7):274-86. · 4.18 Impact Factor
• Source

  Available from: Fabio Di Domenico

  Article: Doxorubicin-induced thymus senescence.

  Rukhsana Sultana, Fabio Di Domenico, Michael Tseng, Jian Cai, Teresa Noel, R Lakshman Chelvarajan, William D Pierce, Ciara Cini, Subbarao Bondada, Daret K St Clair, D Allan Butterfield
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  ABSTRACT: Doxorubicin (DOX) is an anticancer drug used for the treatment of solid tumors. The ability of DOX to treat cancer is not specific to cancer cells; some of the cells that are normal may also become targets of DOX, thereby altering the normal cellular functions and eventual cell loss. DOX effects have been studied in detail in heart because of its ability to cause cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy is not completely understood. One of organs that can be affected by DOX is thymus. DOX treatment leads to degeneration of thymus; however, since thymus undergoes age-dependent degeneration, researchers have understudied the effect of DOX on thymus. In the present investigation, we studied the effects of DOX on thymus, an organ that is important for the T-cell maturation. DOX treatment led to loss of cortical cells, decrease lymphopoiesis and increased the number of Hassells corpuscles, a marker of thymus aging. Proteomics analysis led to identification of a number of thymic proteins whose expression are altered by in vivo DOX treatment. Taken together, these results are consistent with the notion that DOX-treatment leads to thymic senescence.
  Journal of Proteome Research 10/2010; 9(12):6232-41. · 5.11 Impact Factor