Limiting inflammation could significantly impact the course of chronic pancreatitis (CP). To date, there is no standard therapy available to dampen or reverse the inflammatory response associated with CP. Much of the inflammation in CP is driven by elevated interleukin-6 (IL-6) and other cytokines. These soluble factors transmit signals via common intracellular pathways. Most notable are activation of the Jak-STAT pathway. IL-6 also regulates differentiation of macrophages and T cells that fuel inflammation and fibrosis in CP. Thus targeted inhibition of IL-6/Jak-STAT signaling may modulate immune and inflammatory factors in CP and provide therapeutic benefit. Recent published studies from our group and others have demonstrated that pancreatic stellate cells (PSC) are instrumental in driving inflammation in the pancreas. In fact, our data indicate that PSC isolated from mouse models and patients with either pancreatic cancer or CP display striking production of IL-6, and dependence on Jak-STAT signaling for survival. Moreover, inhibition of Jak-STAT signaling decreased proliferation and activation of these sentinel inflammatory cells. These data identify a novel role for the stromal cells as mediators of local and systemic inflammatory changes in pancreatic disorders, and suggest the IL-6/Jak-STAT axis plays a major role in their biologic properties. We hypothesize that IL-6/Jak- STAT signaling in pancreatic stellate cells represents a targetable node relevant to the pathogenesis of chronic pancreatitis.
In Aim 1, we will determine the role of stromal IL-6-mediated signaling in pancreatitis using novel knockout mouse models. Mice with conditional deletion of IL-6 in the stroma will be generated using a fibroblast specific promoter. CP will be induced via a traditional approach of repeated injections of caerulein, or via a novel surgical approach involving ligation of the mid-pancreatic duct, followed by a single caerulein injection. The impact of stromal IL-6 loss on biomarkers of CP will be evaluated. These studies will define the mechanism by which IL-6-mediated signaling, specifically in the PSC compartment, is relevant to the pathology of CP.
In Aim 2, we will evaluate the impact of targeting IL-6/Jak-STAT signaling in murine models of CP. The efficacy of IL-6 neutralizing Ab and the small molecule Jak inhibitor, Ruxolitinib will be evaluated in the caerulein and surgical models of CP. Immune biomarkers altered by inhibition of IL-6/Jak-STAT signaling, and their relevance to pancreatitis will be defined in tissues from these animals. This project is innovative as to date, IL-6 blockade or Jak inhibitors have not been systematically evaluated in patients with CP and only limited studies focused on acinar cells have been published. This approach has strong potential to modulate key downstream pathways that regulate inflammation and disease severity. Thus, there is a high likelihood for rapid translation of already available anti-IL-6 Ab or Jak inhibitors to patients with CP. This project will have hig impact as we will gain necessary pre-clinical data on IL-6/Jak-STAT inhibition in CP that could be leveraged for human clinical trials and subsequent investigations of this pathway within pancreatic disease.
In this application we will study how specialized fibroblasts, or 'stellate cells' present within the pancreas contribute to the debilitating condition known as pancreatitis. We know these cells produce a key immune hormone called interleukin-6 (IL-6) that leads to downstream inflammation in the disease. Our experiments will use both a genetic approach and treatment with clinically-relevant drugs to test whether removing the ability of stellate cells to make IL-6 can improve pancreatitis in animal models. If successful, these studies will improve our understanding of pancreatitis, and identify potential new treatments to limit it.
| Mace, Thomas A; Shakya, Reena; Pitarresi, Jason R et al. (2018) IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 67:320-332 |
| Shapiro, John P; Komar, Hannah M; Hancioglu, Baris et al. (2017) Laser Capture Microdissection of Pancreatic Acinar Cells to Identify Proteomic Alterations in a Murine Model of Caerulein-Induced Pancreatitis. Clin Transl Gastroenterol 8:e89 |
| Hao, Wenrui; Komar, Hannah M; Hart, Phil A et al. (2017) Mathematical model of chronic pancreatitis. Proc Natl Acad Sci U S A 114:5011-5016 |
| Komar, Hannah M; Hart, Phil A; Cruz-Monserrate, Zobeida et al. (2017) Local and Systemic Expression of Immunomodulatory Factors in Chronic Pancreatitis. Pancreas 46:986-993 |
| Komar, Hannah M; Serpa, Gregory; Kerscher, Claire et al. (2017) Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo. Sci Rep 7:1787 |
