Apoptosis

Kinase suppressor of Ras-1 protects intestinal epithelium from cytokine-mediated apoptosis during inflammation. Yan, F. et al. J. Clin. Invest. 114, 1272–1280 (2004).

Inflammatory bowel diseases are characterized by altered cytokine production and increased intestinal epithelial-cell apoptosis. In this paper, Yan et al. show that kinase suppressor of RAS1 (KSR1) protects intestinal epithelial cells from apoptosis induced by tumour-necrosis factor (TNF). The authors observed that KSR1 and its target signalling pathways are activated in inflamed colonic mucosae, whereas KSR1 activity is turned off in normal mucosae. Moreover, KSR1-deficient mice had increased susceptibility to chronic colitis and TNF-induced epithelial-cell apoptosis. This was mediated by the kinase activity of KSR1, as expression of wild-type KSR1, but not kinase-inactive KSR1, restored TNF-induced activation of downstream mediators of anti-apoptotic pathways.

Inflammation

Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Martinon, F., Agostini, L., Meylan, E. & Tschopp, J. Curr. Biol. 14, 1929–1934 (2004).

Assembly of the inflammasome, a key component of which is NALP3, is triggered by ligation of Toll-like receptors (TLRs) with bacterial components, and this results in the activation of caspase-1 and the secretion of interleukin-1β (IL-1β). Similar to TLRs, NALP3 contains leucine-rich repeats, which are frequently used to sense bacterial components. So, can bacteria directly activate the inflammasome? The authors found that bacterial peptidoglycan and its degradation product muramyl dipeptide (MDP), but not lipopolysaccharide, induced NALP3-mediated caspase-1 activation in a TLR-independent manner. Compared with macrophages from controls, macrophages from a patient with Muckle–Wells syndrome, an autoinflammatory disease associated with NALP3 mutations, showed increased IL-1β release in the presence of MDP, indicating that this pathway could be important in the disease.

Cytokines

Interleukin-12-induced interferon-γ production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR). Kusaba, H. et al. J. Biol. Chem. 1 Nov 2004 (doi:10.1074/jbc.M405204200).

Interleukin-12 (IL-12) induces T-cell production of interferon-γ (IFN-γ) by activating cyclosporin A-insensitive signalling pathways. In this paper, the production of IFN-γ by pre-activated human peripheral-blood T cells in response to IL-12 was partially inhibited by another immunosuppressant, rapamycin. Rapamycin decreased IFN-γ transcription, and this correlated with decreased recruitment of the transcription factors STAT3, STAT4 and phosphorylated cJUN. Serine phosphorylation of STAT3 was impaired, and its association with the serine/threonine kinase mammalian target of rapamycin (mTOR) was decreased. These observations led the authors to suggest that treatment of some diseases might require combination therapy to fully suppress T-cell function.