Dc. Caelles Group

Inflammation is a defense response of the organism to stimuli, whether exogenous or endogenous, capable of disturbing the homeostasis of the organism. However, an exacerbated or chronic inflammatory response can lead to the development of pathologies such as septic shock or type 2 diabetes, respectively. Dysfunction in the inflammatory response is usually due to deregulation of the signaling pathways involved in it, such as the JNK pathway. For this reason, the JNK pathway is a front of pharmacological intervention to combat diseases that have activating dysfunctions of the inflammatory response as a component.

The c-Jun N-terminal kinase (JNK) belongs to the mitogen-activated protein kinase (MAKP) family of serine/threonine protein kinases involved in signal transduction. Among other stimuli, the JNK pathway is triggered by pro-inflammatory cytokines. Upon activation, JNK phosphorylates and positively regulates the activity of transcriptional regulators crucial for the inflammatory response, such as the activator protein (AP)-1 complex. In addition, activated JNK also phosphorylates the insulin receptor substrate (IRS)-1/2 and thereby, inhibits its interaction with the insulin receptor (IR). Consequently, JNK pathway activation promotes the down-regulation of the IR signaling, an action that in a chronic pro-inflammatory scenario promotes insulin resistance, which is an early trait in the development of type 2 diabetes. On the other hand, a set of NRs, which includes the glucocorticoid receptor (GR) and the peroxisome proliferator activated receptors (PPARs), has anti-inflammatory properties upon ligand activation. Our major contributions in the field have been to demonstrate that both NRs, upon hormone binding, are able to inhibit JNK activation in response pro-inflammatory stimuli. For the GR, we have shown that JNK inhibition is a mechanism to prevent AP-1 activation and, hence, to block the induction of the inflammatory response transcriptional program. In case of the PPARs, we have shown that JNK pathway inhibition mediates the insulin-sensitizing action of the thiazolidinedione group of drugs and its receptor, the PPAR-g.

We have generated a transgenic mouse model able to activated JNK in a Cre recombinase dependent manner. In these mice we have demonstrated that JNK activation in pancreatic insulin secreting cells blocks insulin secretion in response to increases in glycaemia. This blockade is due to the JNK-induced inhibition of the IR signaling that blunts insulin auto/paracrine action in Langerhans islets. We plan to use these mice to further study the JNK pathway role(s) on insulin action(s) in different tissues and conditions and in the response to anti-diabetic drugs. In addition, this mouse model will allow us to study the role of JNK activation in the development of resistances to therapy which are relevant in clinics, such as the glucocorticoid resistance.