clc is co-expressed with clf or cntfr in developing mouse muscles

BACKGROUND: The ciliary neurotrophic factor (CNTF) receptor is composed of two signalling receptor chains, gp130 and the leukaemia inhibitory factor receptor, associated with a non-signalling CNTF binding receptor α component (CNTFR). This tripartite receptor has been shown to play important roles in the development of motor neurons, but the identity of the relevant ligand(s) is still not clearly established. Recently, we have identified two new ligands for the CNTF receptor complex. These are heterodimeric cytokines composed of cardiotrophin-like cytokine (CLC) associated either with the soluble receptor subunit cytokine-like factor-1 (CLF) or the soluble form of the binding receptor itself (sCNTFR). RESULTS: Here we show that, during development, clc is expressed in lung, kidney, vibrissae, tooth, epithelia and muscles during the period of development corresponding to when motoneuron loss is observed in mice lacking a functional CNTF receptor. In addition, we demonstrate that it is co-expressed at the single cell level with clf and cntfr, supporting the idea that CLC might be co-secreted with either CLF or sCNTFR. CONCLUSION: This expression pattern is in favor of CLC, associated either with CLF or sCNTFR, being an important player in the signal triggered by the CNTF receptor being required for motoneuron development

TLR4-induced IFN-γ production increases TLR2 sensitivity and drives Gram-negative sepsis in mice

Gram-negative bacterial infection is a major cause of sepsis and septic shock. An important inducer of inflammation underlying both syndromes is the cellular recognition of bacterial products through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). We identified a novel antagonistic mAb (named 1A6) that recognizes the extracellular portion of the TLR4–MD-2 complex. If applied to mice before infection with clinical isolates of Salmonella enterica or Escherichia coli and subsequent antibiotic therapy, 1A6 prevented otherwise fatal shock, whereas application of 1A6 after infection was ineffective. In contrast, coapplication of 1A6 and an anti-TLR2 mAb up to 4 h after infection with Gram-negative bacteria, in combination with the start of antibiotic therapy (mimicking clinical conditions), provided robust protection. Consistent with our findings in mice, dual blockade of TLR2 and TLR4 inhibited TNF-α release from human peripheral blood mononuclear cells upon Gram-negative bacterial infection/antibiotic therapy. Both murine splenocytes and human PBMCs released IFN-γ in a TLR4-dependent manner, leading to enhanced surface TLR2 expression and sensitivity for TLR2 ligands. Our results implicate TLR2 as an important, TLR4-driven sensor of Gram-negative bacterial infection and provide a rationale for blockade of both TLRs, in addition to antibiotic therapy for the treatment of Gram-negative bacterial infection

‘NOT A RELIGIOUS STATE’ A study of three Indonesian religious leaders on the relation of state and religion

This article explores the concept of a ‘secular state’ offered by three Indonesian religious leaders: a Catholic priest, Nicolaus Driyarkara (1913–1967), and two Muslim intellectuals who were also state officials, Mukti Ali (1923–2004) and Munawir Sjadzali (1925–2004). All three, who represented the immediate generation after the revolution for Indonesian independence from the Dutch (1945), defended the legitimacy of a secular state for Indonesia based on the state ideology Pancasila (Five Principles of Indonesia). In doing so, they argued that a religious state, for example an Islamic state, is incompatible with a plural nation that has diverse cultures, faiths, and ethnicities. The three also argued that the state should remain neutral about its citizens’ faith and should not be dominated by a single religion, i.e. Islam. Instead, the state is obliged to protect all religions embraced by Indonesians. This argument becomes a vital foundation in the establishment of Indonesia’s trajectory of unique ‘secularisation’. Whilst these three intellectuals opposed the idea of establishing a religious or Islamic state in Indonesia, it was not because they envisioned the decline of the role of religion in politics and the public domain but rather that they regarded religiosity in Indonesia as vital in nation building within a multi-religious society. In particular, the two Muslim leaders used religious legitimacy to sustain the New Order’s political stability, and harnessed state authority to modernise the Indonesian Islamic community

Cover and contents : “Proceedings of the 11th CEReS Symposium on Enviromental Remote Sensing” February 23, 2009

2009年2月23日（月） 於 千葉大学けやき会

Harnessing receptor clustering in lipid rafts to tailor the inhibitory effects of monoclonal antibodies to specific cell types

Certain cell signaling pharmaceutical targets have the potential to provide substantial clinical benefit when inhibited on some cell types yet elicit unwanted collateral damage when impeded on others. Thus, the appropriate therapeutic strategy for this situation would be to block preferentially receptor activation on the desired cell set. Taking advantage of the clustering within lipid rafts of toll-like receptor 4 (TLR4) and Fc gamma receptors (FcγR) during TLR4 activation, we have identified a mechanism that allows an antibody to block more favorably signaling on leukocytes, cells that underlie acute and chronic inflammatory processes. The anti-TLR4 monoclonal antibody (mAb), Hu 15C1, co-engages TLR4 and FcγRs to enhance its inhibitory potency via an avidity effect on FcγR-bearing cells. This novel mechanism of action allows the mAb to block efficiently TLR4 activation on FcγR-bearing inflammatory cells, while limiting the duration of effect on cells lacking FcγRs. As receptor clustering in lipid rafts is a common phenomenon, this mechanism could be exploited to anchor similar receptor-targeting mAbs or formats bearing an antibody Fc domain to desired cell types

Toll-Like Receptor 4 on both Myeloid Cells and Dendritic Cells Is Required for Systemic Inflammation and Organ Damage after Hemorrhagic Shock with Tissue Trauma in Mice

Trauma combined with hemorrhagic shock (HS/T) leads to systemic inflammation, which results in organ injury. Toll-like Receptor 4 (TLR4)-signaling activation contributes to the initiation of inflammatory pathways following HS/T but its cell-specific roles in this setting are not known. We assessed the importance of TLR4 on leukocytes of myeloid lineage and dendritic cells (DCs) to the early systemic inflammatory response following HS/T. Mice were subjected to HS/T and 20 inflammatory mediators were measured in plasma followed by Dynamic Bayesian Network (DBN) Analysis. Organ damage was assessed by histology and plasma ALT levels. The role of TLR4 was determined using TLR4−/−, MyD88−/−, and Trif−/− C57BL/6 (B6) mice, and by in vivo administration of a TLR4-specific neutralizing monoclonal antibody (mAb). The contribution of TLR4 expressed by myeloid leukocytes and DC was determined by generating cell-specific TLR4−/− B6 mice, including Lyz-Cre × TLR4loxP/loxP, and CD11c-Cre × TLR4loxP/loxP B6 mice. Adoptive transfer of bone marrow-derived TLR4+/+ or TLR4−/− DC into TLR4−/− mice confirmed the contribution of TLR4 on DC to the systemic inflammatory response after HS/T. Using both global knockout mice and the TLR4-blocking mAb 1A6 we established a central role for TLR4 in driving systemic inflammation. Using cell-selective TLR4−/− B6 mice, we found that TLR4 expression on both myeloid cells and CD11chigh DC is required for increases in systemic cytokine levels and organ damage after HS/T. We confirmed the capacity of TLR4 on CD11chigh DC to promote inflammation and liver damage using adoptive transfer of TLR4+/+ conventional (CD11chigh) DC into TLR4−/− mice. DBN inference identified CXC chemokines as proximal drivers of dynamic changes in the circulating levels of cytokines/chemokines after HS/T. TLR4 on DC was found to contribute selectively to the elevations in these proximal drivers. TLR4 on both myeloid cells and conventional DC is required for the initial systemic inflammation and organ damage in a mouse model of HS/T. This includes a role for TLR4 on DC in promoting increases in the early inflammatory networks identified in HS/T. These data establish DC along with macrophages as essential to the recognition of tissue damage and stress following tissue trauma with HS