Innate Immune Response of Human Alveolar Macrophages during Influenza A Infection

Alveolar macrophages (AM) are one of the key cell types for initiating inflammatory and immune responses to influenza virus in the lung. However, the genome-wide changes in response to influenza infection in AM have not been defined. We performed gene profiling of human AM in response to H1N1 influenza A virus PR/8 using Affymetrix HG-U133 Plus 2.0 chips and verified the changes at both mRNA and protein levels by real-time RT-PCR and ELISA. We confirmed the response with a contemporary H3N2 influenza virus A/New York/238/2005 (NY/238). To understand the local cellular response, we also evaluated the impact of paracrine factors on virus-induced chemokine and cytokine secretion. In addition, we investigated the changes in the expression of macrophage receptors and uptake of pathogens after PR/8 infection. Although macrophages fail to release a large amount of infectious virus, we observed a robust induction of type I and type III interferons and several cytokines and chemokines following influenza infection. CXCL9, 10, and 11 were the most highly induced chemokines by influenza infection. UV-inactivation abolished virus-induced cytokine and chemokine response, with the exception of CXCL10. The contemporary influenza virus NY/238 infection of AM induced a similar response as PR/8. Inhibition of TNF and/or IL-1β activity significantly decreased the secretion of the proinflammatory chemokines CCL5 and CXCL8 by over 50%. PR/8 infection also significantly decreased mRNA levels of macrophage receptors including C-type lectin domain family 7 member A (CLEC7A), macrophage scavenger receptor 1 (MSR1), and CD36, and reduced uptake of zymosan. In conclusion, influenza infection induced an extensive proinflammatory response in human AM. Targeting local components of innate immune response might provide a strategy for controlling influenza A infection-induced proinflammatory response in vivo

The Conservative party, fascism and anti-fascism 1918-1939

The interwar Conservative party provides a challenge for recent historical definitions of British anti-fascism. Distinctions between ‘non-fascism’ and ‘anti-fascism’ and between ‘passive anti-fascism’ and ‘active anti-fascism’ have been valuable in stimulating debate about the character of resistance to fascism, but as Andrzej Olechnowicz has demonstrated these categories have been used to give priority to the political left – the Communist party in some accounts, the Labour party in others – while overlooking the substantial range of ‘liberal’ anti-fascism that included numerous Liberals and Conservatives as well as Labour figures. His focus is on cross-party or non-party organisations, and as Helen McCarthy has also shown such associations which promoted citizenship and other democratic causes are certainly a notable and under-studied feature of interwar British political culture. The Conservative party, however, raises a different range of definitional issues, and not only because it formed the main element in the most important cross-party body, the National government formed with the main Liberal groups and a few Labour leaders in 1931. Notoriously, a number of Conservatives admired fascism in one or more of its British or foreign forms, and some historians have taken this as indicative of wider Conservative sympathies. Yet the party as a whole was, at the very least, the largest ‘non-fascist’ political organisation. There are several reasons to go further. The Conservative party’s dominance of not just most of the political right but also large expanses of the political centre constituted a more decisive barrier to the growth of British fascism than the explicitly anti-fascist bodies of the political left. As many of its actions and statements had anti-fascist effects, the party might well be categorised as ‘passive anti-fascist’. Further, from 1933 leading Conservatives mounted an ideological and moral resistance towards dictatorship and totalitarianism, which should certainly be classified as ‘active anti-fascism’. In considering the interwar Conservative party’s attitudes towards fascism and more especially British fascists, the ‘party’ is taken here to mean its leaders, its ministers in Conservative and coalition governments, the strategists and publicists in its national organisation, Conservative MPs, those Conservative peers significant in national politics, and regional and local officials – rather than the penumbra of journalists and other publicists who expressed various Conservative opinions, but very few of whom were important for Conservative politicians. As a necessary preliminary, the first section of this essay will comment on suggestions that the Conservative party contained a significant pro-fascist element, and that decisions by the party’s leaders in the mid 1930s were affected by fears of losing support to the British fascist groups. It will then be argued that the Conservative party provided a considerable indirect resistance to fascism. While pursuing its main political concerns, the party had the largest role in preserving stable government, maintaining confidence in existing institutions, and containing challenges from the far left which might have provoked greater interest in fascism. At the same time it accommodated or emasculated various radical ‘right’ groups which might conceivably have defected to fascism. The third section will consider Conservative anti-fascism in the direct sense, the expression of arguments and values in opposition to British and international fascism

Molecular Pathways in Virus-Induced Cytokine Production

Virus infections induce a proinflammatory response including expression of cytokines and chemokines. The subsequent leukocyte recruitment and antiviral effector functions contribute to the first line of defense against viruses. The molecular virus-cell interactions initiating these events have been studied intensively, and it appears that viral surface glycoproteins, double-stranded RNA, and intracellular viral proteins all have the capacity to activate signal transduction pathways leading to the expression of cytokines and chemokines. The signaling pathways activated by viral infections include the major proinflammatory pathways, with the transcription factor NF-κB having received special attention. These transcription factors in turn promote the expression of specific inducible host proteins and participate in the expression of some viral genes. Here we review the current knowledge of virus-induced signal transduction by seven human pathogenic viruses and the most widely used experimental models for viral infections. The molecular mechanisms of virus-induced expression of cytokines and chemokines is also analyzed