Inhibition of Secretion of Interleukin (IL)-12/IL-23 Family Cytokines by 4-Trifluoromethyl-celecoxib Is Coupled to Degradation via the Endoplasmic Reticulum Stress Protein HERP

Interleukin-12 (IL-12), p80, and IL-23 are structurally related cytokines sharing a p40 subunit. We have recently demonstrated that celecoxib and its COX-2-independent analogue 4-trifluoromethyl-celecoxib (TFM-C) inhibit secretion but not transcription of IL-12 (p35/p40) and p80 (p40/p40). This is associated with a mechanism involving altered cytokine-chaperone interaction in the endoplasmic reticulum (ER). In the present study, we found that celecoxib and TFM-C also block secretion of IL-23 (p40/p19 heterodimers). Given the putative ER-centric mode of these compounds, we performed a comprehensive RTPCR analysis of 23 ER-resident chaperones/foldases and associated co-factors. This revealed that TFM-C induced 1.5-3-fold transcriptional up-regulation of calreticulin, GRP78, GRP94, GRP170, ERp72, ERp57, ERdj4, and ERp29. However, more significantly, a 7-fold up-regulation of homocysteine-inducible ER protein (HERP) was observed. HERP is part of a high molecular mass protein complex involved in ER-associated protein degradation (ERAD). Using co-immunoprecipitation assays, we show that TFM-C induces protein interaction of p80 and IL-23 with HERP. Both HERP siRNA knockdown and HERP overexpression coupled to cycloheximide chase assays revealed that HERP is necessary for degradation of intracellularly retained p80 by TFM-C. Thus, our data suggest that targeting cytokine folding in the ER by small molecule drugs could be therapeutically exploited to alleviate in appropriate inflammation in autoimmune conditions.

The effects of sudden paternal death on young people and their family relationships: some implications for practice

The importance for children and young people to be able to communicate openly about the death of a parent is evident from the literature. This small-scale investigation uses a case-study approach to illustrate the impact on siblings of the sudden death of a father. The abundance of comments from the young people in the study such as “talking is the only thing that helps” and “everybody has to get it out” emphasise the important role of communication within the family. Children tend to take their emotional cues from other family members and, paradoxically, restrict communication of their own grief in an attempt to protect others. Even if painful in the short term, certain lines of communication may need to be established if family members are to be able to support each other in dealing with the distressing experience of the death in a healthy manner. The study suggests that those who work with young people in such circumstances should take cognisance of these issues.

Family support, social capital, resilience and adolescent coping

All too often young people are excluded in practice from the general policy and professional consensus that partnership and participation should underpin work with children, young people and their families. If working with troubled and troublesome young people is to be based on family support, it will require not only the clear statement of that policy but also demonstration that it can be applied in practice. Achieving that involves setting out a plausible theory of change that can be rigorously evaluated. This paper suggests a conceptual model that draws on social support theory to harness the ideas of social capital and resilience in a way that can link formal family support interventions to adolescent coping. Research with young people attending three community-based projects for marginalized youth is used to illustrate how validated tools can be used to measure and document the detail of support, resilience, social capital and coping in young people's lives. It is also suggested that there is sufficient fit between the findings emerging from the study and the model to justify the model being more rigorously tested.

Home curation versus teenage photography: Photo displays in the family home

In this paper we report an empirical study of the photographic portrayal of family members at home. Adopting a social psychological approach and focusing oil intergenerational power dynamics, our research explores the use of domestic photo displays in family representation. Parents and their teenagers from eight families in the south of England were interviewed at home about their interpretations of both stored and displayed photos within the home. Discussions centred on particular photographs found by the participants to portray self and family in different ways. The findings show that public displays of digital photos are still curated by mothers of the households, but with more difficulty and less control all with analogue photos. In addition, teenagers both contribute and comply with this curation within the home, whilst at the same time developing additional ways of presenting their families and themselves online that are 'unsupervised' by the curator. We highlight the conflict of interest that is at play within teen and parent practices and consider the challenges that this presents for supporting the representation of family through the design of photo display technology. (C) 2009 Elsevier Ltd. All rights reserved.