Implication of STAT1 and STAT3 transcription factors in the response to superantigens

The activation of STAT1 and STAT3 in response to SEB was analyzed in spleen of Balb/c mice. The intraperitoneal injection of the superantigen SEB activated STAT1 and STAT3 in spleen. Activated STAT1 almost completely disappeared in 24 h even though activated STAT3 was present for more than 48 h after SEB injection. Cyclosporine A was able to block the initial STAT1 activation, but STAT3 activation was only partially affected. SEB also increased the mRNA levels for STAT1, STAT3 and SOCS1. When a second injection with SEB was given 72 h after the first stimulus, STAT1 activation was much lower than that observed after the first stimulation with SEB and no increase in the STAT1 mRNA level was observed. Nevertheless, after this second injection, STAT3 was again activated without any significant interference from the first stimulus and the STAT3 and SOCS1 mRNA levels again increased. These data indicate that a first stimulation with superantigen re-programs cells so that they respond to a second stimulation in a different way. Understanding the mechanisms implicated in this re-programming is basic for designing therapeutic strategies in processes such as septic shock.     

Determinants governing the potency of STAT3 activation via the individual STAT3-recruiting motifs of gp130

In recent years, the elucidation of the structures of many signalling molecules has allowed new insights into the molecular mechanisms that govern signal transduction events. In the field of cytokine signalling, the solved structures of cytokine/receptor complexes and of key components involved in signal transduction such as STAT factors or the tyrosine phosphatase SHP2 have broadened our understanding of the molecular basis of the signalling events and provided key information for the rational design of therapeutic approaches to modulate or block cytokine signal transduction. Unfortunately, no structural data on the intracellular parts of cytokine receptors are available. The exact molecular mechanism underlying one of the first steps in signal transduction, namely the recruitment of signalling components to the cytoplasmic parts of cytokine receptors, remains elusive. Here we investigated possible mechanisms underlying the different potency of the STAT3-activating motifs of gp130 after IL-6 stimulation. Our data indicate that the extent of STAT3 activation by the different receptor motifs is not influenced by structural features such as contacts between the two gp130 chains. In addition, the proximity of the negatively regulating motif around tyrosine Y759 to the different STAT3-recruiting motifs does not seem to be responsible for their differential capacity to activate STAT3. However, the potency of a specific motif to activate STAT3 directly reflects the affinity for the binding of STAT3 to this motif.     

A molecular model for the differential activation of STAT3 and STAT6 by the herpesviral oncoprotein tip

Constitutive STAT signaling provides growth promoting signals in many forms of malignancy. We performed molecular modeling and molecular dynamics studies of the interaction between the regulatory Src homology 2 (SH2) domains of STAT3 and 6 with phosphorylated peptides of the herpesviral oncoprotein Tip, which facilitates Src kinase mediated STAT-activation and T cell proliferation. The studies give insight into the ligand binding specificity of the STAT SH2 domains and provide the first model for the differential activation of STAT3 or STAT6 by two distinct regions of the viral Tip protein. The biological relevance of the modeled interactions was then confirmed by activation studies using corresponding recombinant oncoproteins, and finally by respective recombinant viruses. The functional data give experimental validation of the molecular dynamics study, and provide evidence for the involvement of STAT6 in the herpesvirus induced T cell proliferation.     

Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis

Mechanisms that initiate lupus nephritis and cause progression to end-stage renal disease remain poorly understood. In this study, we show that lupus-prone New Zealand Mixed 2410 mice that develop a severe glomerulosclerosis and rapidly progressive renal disease overexpress IL-4 in vivo. In these mice, STAT6 deficiency or anti-IL-4 Ab treatment decreases type 2 cytokine responses and ameliorates kidney disease, particularly glomerulosclerosis, despite the presence of high levels of IgG anti-dsDNA Abs. STAT4 deficiency, however, decreases type 1 and increases type 2 cytokine responses, and accelerates nephritis, in the absence of high levels of IgG anti-dsDNA Abs. Thus, STAT6 and IL-4 may selectively contribute to the development of glomerulosclerosis, whereas STAT4 may play a role in autoantibody production.