Role of tpI2 on Acute Pancreatitis

Tumor Progression Locus-2 (Tpl2) is a proto-oncogene, first cloned in 1993 (PNAS, 1993, 90:2251) that codes for a serine/threonine protein kinase. Initial interest in Tpl2 focused on its role in oncogenesis but, more recently, a number of studies have shown that Tpl2 also plays an important role in regulating inflammatory processes.

Tpl2 over-expression has been noted to cause activation of ERK, JNK, SAPK, and p38MAPK signal transduction pathways and to activate the transcription factors NFAT and NF-kB. Studies using Tpl2 deficient murine models (Cell, 2000, 103:1071) have indicated that deletion of Tpl2 prevents transport of TNF-a mRNA from the nucleus to the cytoplasm. Deletion of Tpl2 interferes with LPS-stimulated PGE2 synthesis by preventing CREB-induced induction of COX 2. It also interferes with LPS-induced MAPK activation. Recently, it was shown that Tpl2 is a MAPKKK activating MKK4 (J. Biol. Chem. 2005, 280:23748).

Taken together, these previously published studies strongly indicate that Tpl2 plays an important role in regulating inflammatory processes, particularly those involved in the generation and/or action of TNF-a. Acute pancreatitis and its experimental rodent model induced by supramaximal secretagogue stimulation are characterized by an intense inflammatory response, both in the pancreas and in the lung, and TNF-a is believed to be one of many pro-inflammatory factors which regulate the severity of this disease.

The role of Tpl2 in regulating pancreatitis and pancreatitis-associated lung injury has not been previously addressed but, based on the findings noted in Tpl2 studies of other inflammatory conditions, it is not surprising that our preliminary studies found that Tpl2 deletion profoundly alters the inflammatory response in experimental pancreatitis. It is tempting to speculate, based on our preliminary observations, that therapeutic interventions targeting Tpl2 might favorably affect the natural history of clinical acute pancreatitis. The design of such strategies, however, would be considerably aided by elucidation of the mechanisms and cell types involved in Tpl2-regulated inflammation during pancreatitis and that is the goal of the current project.

Results on these studies have been published in the Journal of Biological Chemistry. Tumor Progression Locus-2 Is a Critical Regulator of Pancreatic and Lung Inflammation during Acute Pancreatitis