BADERC-Zhijun Luo

Barbara Nikolajczyk, Ph.D

Mechanisms that control systemic inflammation in type 2 diabetes

Projects in the Nikolajczyk lab focus on understanding how immune system cells modulate systemic inflammation in type 2 diabetes patients. Inflammation is strongly implicated in the most dire complications of type 2 diabetes, including cardiovascular disease and stroke. We are focusing on two cell types that promote inflammation in these patients: monocytes and B cells.

Project 1: Recent work indicates that blocking activity of the pro-inflammatory cytokine IL-1b through infusion of a natural inhibitor of IL-1b, IL-1 receptor antagonist (IL-1ra), decreased systemic inflammation in type 2 diabetes patients. IL-1ra infusion also increased insulin sensitivity in the same study. Overall, this work indicated that decreasing IL-1b production/activity using methods that are less invasive yet more stable than IL-1ra infusion will be effective in combatting the many complications that account for both morbidity and mortality associated with type 2 diabetes. Monocytes are well known to produce significant amounts of pro-inflammatory cytokines and are potent producers of IL-1b. Our most recent work recapitulates demonstrations that fresh ex vivo monocytes from type 2 diabetics hyper-produce IL-1b. These cell also hyper-produce IL-1b in response to stimulation. Recent time course analyses in the Nikolajczyk lab demonstrate that although IL-1b production by monocytes from diabetic patients vs. healthy donors is elevated, peak IL-1b production is significantly delayed (p<0.03) in monocytes from type 2 diabetics compared to healthy donors. This findings indicates that the fundamental mechanisms regulating IL-1b production are altered in diabetes. Our analysis of interactions between transcription factors and the IL-1b promoter in monocytes from type 2 diabetics is beginning to identify protein/DNA and protein/protein interactions that explain both IL-1b hyper-production and the delayed peak of IL-1b production. The goal of this work is to first fully characterize differences suggested by our ongoing work, then to design small molecule inhibitors that would block key events in IL-1b production by monocytes from type 2 diabetic patients.

Project 2: A second focus of the Nikolajczyk lab is to understand how B cells contribute to type 2 diabetes inflammation in individuals with and without confounding periodontal disease. We have found B cells in type 2 diabetes patients and in periodontal disease patients (who are normoglycemic) have elevated responses to toll-like receptor ligands and that cytokine production is activated/blocked by TLR ligand cross-talk. Therefore, these B cells are fundamentally altered such that they unexpectedly respond to inflammatory stimuli. Ongoing analyses are characterizing these responses as well as the underlying molecular mechanisms driving them. Preliminary evidence suggests B cells from these two inflammatory disease cohorts respond differently to toll-like receptor (TLR) ligands. Furthermore, our studies suggest that B cells will respond differently to anti-inflammatory treatments as compared to monocytes, raising the possibility that treatments based on monocyte studies alone will be prone to unexpected outcomes in clinical trials involving alteration of TLR protein function. Our studies are aimed at identifying targets for alleviating the over-production of pro-inflammatory cytokines generally associated with the devastating complications of isolated and co-occurring systemic inflammatory diseases by focusing on an unappreciated source of cytokines in diabetics, B cells.

References:

Liang, MD, Zhang, Y, McDevit, DC, Marecki, S and Nikolajczyk, BS. 2006. The IL-1b gene is transcribed from a poised promoter architecture in monocytes. J. Biol. Chem. 281:9227-9237. PMID: 16439360.
Zhang, Y, Saccani, S, Hyunjin Shin and Nikolajczyk, BS. 2008. Dynamic protein associations define two phases of IL-1b transcriptional activation J. Immunol. 181:503-512. PMID: 18566416
Shin*, H, Zhang*, Y, Jagannathan, M, Hasturk, H, Kantarci, A, Liu, H, Van Dyke, TE, Ganley-Leal, LM¡, and Nikolajczyk, BS¡. 2009. B cells from periodontal disease patients express surface Toll-like Receptor 4 (Accepted, Journal of Leukocyte Biology). *¡ Equal contribution.
Noronha, AM, Liang, YM, Hetzel, J, Hasturk, H, Kantarci, A, Stucci, A, Zhang, Y, Farraye, FA, Nikolajczyk, BS, and Ganley-Leal, LM. Hyper-activated B cells in human inflammatory bowel disease. (Submitted).
Jagannathan, M, Hasturk, H, Liang, YM, Shin, H, McDonnell, ME, Rubin, D, Van Dyke, TE, Ganley-Leal, LM and Nikolajczyk, BS. Toll-like Receptor cross-talk differentially regulates cytokine production by B cells from systemic inflammatory disease patients (Submitted).






			Barbara Nikolajczyk, Ph.D Mechanisms that control systemic inflammation in type 2 diabetes Projects in the Nikolajczyk lab focus on understanding how immune system cells modulate systemic inflammation in type 2 diabetes patients. Inflammation is strongly implicated in the most dire complications of type 2 diabetes, including cardiovascular disease and stroke. We are focusing on two cell types that promote inflammation in these patients: monocytes and B cells. Project 1: Recent work indicates that blocking activity of the pro-inflammatory cytokine IL-1b through infusion of a natural inhibitor of IL-1b, IL-1 receptor antagonist (IL-1ra), decreased systemic inflammation in type 2 diabetes patients. IL-1ra infusion also increased insulin sensitivity in the same study. Overall, this work indicated that decreasing IL-1b production/activity using methods that are less invasive yet more stable than IL-1ra infusion will be effective in combatting the many complications that account for both morbidity and mortality associated with type 2 diabetes. Monocytes are well known to produce significant amounts of pro-inflammatory cytokines and are potent producers of IL-1b. Our most recent work recapitulates demonstrations that fresh ex vivo monocytes from type 2 diabetics hyper-produce IL-1b. These cell also hyper-produce IL-1b in response to stimulation. Recent time course analyses in the Nikolajczyk lab demonstrate that although IL-1b production by monocytes from diabetic patients vs. healthy donors is elevated, peak IL-1b production is significantly delayed (p<0.03) in monocytes from type 2 diabetics compared to healthy donors. This findings indicates that the fundamental mechanisms regulating IL-1b production are altered in diabetes. Our analysis of interactions between transcription factors and the IL-1b promoter in monocytes from type 2 diabetics is beginning to identify protein/DNA and protein/protein interactions that explain both IL-1b hyper-production and the delayed peak of IL-1b production. The goal of this work is to first fully characterize differences suggested by our ongoing work, then to design small molecule inhibitors that would block key events in IL-1b production by monocytes from type 2 diabetic patients. Project 2: A second focus of the Nikolajczyk lab is to understand how B cells contribute to type 2 diabetes inflammation in individuals with and without confounding periodontal disease. We have found B cells in type 2 diabetes patients and in periodontal disease patients (who are normoglycemic) have elevated responses to toll-like receptor ligands and that cytokine production is activated/blocked by TLR ligand cross-talk. Therefore, these B cells are fundamentally altered such that they unexpectedly respond to inflammatory stimuli. Ongoing analyses are characterizing these responses as well as the underlying molecular mechanisms driving them. Preliminary evidence suggests B cells from these two inflammatory disease cohorts respond differently to toll-like receptor (TLR) ligands. Furthermore, our studies suggest that B cells will respond differently to anti-inflammatory treatments as compared to monocytes, raising the possibility that treatments based on monocyte studies alone will be prone to unexpected outcomes in clinical trials involving alteration of TLR protein function. Our studies are aimed at identifying targets for alleviating the over-production of pro-inflammatory cytokines generally associated with the devastating complications of isolated and co-occurring systemic inflammatory diseases by focusing on an unappreciated source of cytokines in diabetics, B cells. References: Liang, MD, Zhang, Y, McDevit, DC, Marecki, S and Nikolajczyk, BS. 2006. The IL-1b gene is transcribed from a poised promoter architecture in monocytes. J. Biol. Chem. 281:9227-9237. PMID: 16439360. Zhang, Y, Saccani, S, Hyunjin Shin and Nikolajczyk, BS. 2008. Dynamic protein associations define two phases of IL-1b transcriptional activation J. Immunol. 181:503-512. PMID: 18566416 Shin, H, Zhang, Y, Jagannathan, M, Hasturk, H, Kantarci, A, Liu, H, Van Dyke, TE, Ganley-Leal, LM¡, and Nikolajczyk, BS¡. 2009. B cells from periodontal disease patients express surface Toll-like Receptor 4 (Accepted, Journal of Leukocyte Biology). ¡ Equal contribution. Noronha, AM, Liang, YM, Hetzel, J, Hasturk, H, Kantarci, A, Stucci, A, Zhang, Y, Farraye, FA, Nikolajczyk, BS,* and Ganley-Leal, LM. Hyper-activated B cells in human inflammatory bowel disease. (Submitted). Jagannathan, M, Hasturk, H, Liang, YM, Shin, H, McDonnell, ME, Rubin, D, Van Dyke, TE, Ganley-Leal, LM and Nikolajczyk, BS. Toll-like Receptor cross-talk differentially regulates cytokine production by B cells from systemic inflammatory disease patients (Submitted).