Integrated network analysis of transcriptomic and proteomic data in psoriasis

Background  

Psoriasis is complex inflammatory skin pathology of autoimmune origin. Several cell types are perturbed in this pathology, and underlying signaling events are complex and still poorly understood.     

Cytokine and molecular networks in sepsis cases: a network biology approach

Background

Sepsis is a life-threatening condition of organ dysfunction caused by a dysregulated host immune response to infection. We performed network analysis of cytokine molecules and compared network structures between a systematic inflammatory response syndrome (SIRS) or normal control (NC) group and a sepsis group.

Results

We recruited SIRS (n = 33) and sepsis (n = 89) patients from electronic medical records (EMR) according to whether data on PCT, CRP, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17, IL-22, TNF-α, and IFN-γ levels were available. From the public GEO dataset, GSE66099, GSE9960, GSE95233, GSE57065 were downloaded. Genes corresponding to 15 molecules were extracted from an expression array. A correlation matrix was formed for the 15 molecules and statistically significant molecular pairs were used as pairs for network analysis of coexpression. The number of molecular or gene expression pairs significantly correlated among the SIRS or control and sepsis groups are as follows for datasets: EMR, 15 and 15; GEO66099-1, 13 and 15; GEO9960, 13 and 11; GSE95233, 13 and 8; GSE66099-2, 15 and 14; GSE57065, 14 and 13, respectively. Network analysis revealed that network diameter, number of nodes and shortest path were equal to or lower in the sepsis group.

Conclusions

The coexpression network in sepsis patients was relatively small sized and had lower shortest paths compared with the SIRS group or healthy control group. Cytokines with one degree (k = 1) are increased in sepsis group compared with SIRS or healthy control group. IL-9 and IL-2 were not included in network of sepsis group indicating that these cytokines showed no correlation with other cytokines. These data might imply that cytokines tend to be dysregulated in the sepsis group compared to that of SIRS or normal control groups

     

Cytokine milieu of atopic dermatitis,as compared to psoriasis,skin prevents induction of innate immune response genes

Atopic dermatitis (AD) and psoriasis are the two most common chronic skin diseases. However patients with AD, but not psoriasis, suffer from frequent skin infections. To understand the molecular basis for this phenomenon, skin biopsies from AD and psoriasis patients were analyzed using GeneChip microarrays. The expression of innate immune response genes, human beta defensin (HBD)-2, IL-8, and inducible NO synthetase (iNOS) was found to be decreased in AD, as compared with psoriasis, skin (HBD-2, p = 0.00021; IL-8, p = 0.044; iNOS, p = 0.016). Decreased expression of the novel antimicrobial peptide, HBD-3, was demonstrated at the mRNA level by real-time PCR (p = 0.0002) and at the protein level by immunohistochemistry (p = 0.0005). By real-time PCR, our data confirmed that AD, as compared with psoriasis, is associated with elevated skin production of Th2 cytokines and low levels of proinflammatory cytokines such as TNF-alpha, IFN-gamma, and IL-1beta. Because HBD-2, IL-8, and iNOS are known to be inhibited by Th2 cytokines, we examined the effects of IL-4 and IL-13 on HBD-3 expression in keratinocyte culture in vitro. We found that IL-13 and IL-4 inhibited TNF-alpha- and IFN-gamma-induced HBD-3 production. These studies indicate that decreased expression of a constellation of antimicrobial genes occurs as the result of local up-regulation of Th2 cytokines and the lack of elevated amounts of TNF-alpha and IFN-gamma under inflammatory conditions in AD skin. These observations could explain the increased susceptibility of AD skin to microorganisms, and suggest a new fundamental rule that may explain the mechanism for frequent infection in other Th2 cytokine-mediated diseases.     

Cytokine pharmacogenetics

Genetic variation plays a significant role in the normal functioning of the immune system, and also in the interaction between many common drugs and cellular pathways. With a growing number of cytokine-based therapies now in mainstream clinical use, the prospect of targeting these agents to the individuals likely to benefit from them most is an appealing one. This review outlines the potential clinical impact of cytokine pharmacogenetics in targeting these therapies to individuals with favourable genetic profiles. The use of such approaches may have important pharmacoeconomic benefits and lead to improved therapeutic profiles for these treatments.     

Biogeography revisited with network theory: retracing the history of hydrothermal vent communities

Defining biogeographic provinces to understand the history and evolution of communities associated with a given kind of ecosystem is challenging and usually requires a priori assumptions to be made. We applied network theory, a holistic and exploratory method, to the most complete database of faunal distribution available on oceanic hydrothermal vents, environments which support fragmented and unstable ecosystems, to infer the processes driving their worldwide biogeography. Besides the identification of robust provinces, the network topology allowed us to identify preferential pathways that had hitherto been overlooked. These pathways are consistent with the previously proposed hypothesis of a role of plate tectonics in the biogeographical history of hydrothermal vent communities. A possible ancestral position of the Western Pacific is also suggested for the first time. Finally, this work provides an innovative example of the potential of network tools to unravel the biogeographic history of faunal assemblages and to supply comprehensive information for the conservation and management of biodiversity.     

The concept of the CCN protein family revisited: a centralized coordination network

The wide array of biological properties attributed to the CCN family of proteins (Perbal in Lancet 363(9402):62–64, 2004) led me to reconsider the possible relationship and roles that these proteins may play as a team, instead of acting on their own as individual regulators in various signaling pathways. The dynamic model which I present in this review stems from the contribution of the biological properties that we established for CCN3, one of the three founding members of the CCN family, which was identified by our group as the first CCN protein showing growth inhibitory properties (1992), expressed mainly in quiescent cells (1996), and showing anti-tumor activities in several cellular models both ex vivo and in vivo. At the present time CCN3 is the only member of the family that has been reported to negatively act on the progression of the cell cycle. The unique dual localisation of CCN3 in the nucleus and outside cells, either at the membrane or in the extracellular matrix, that I first established in 1999, and that now appears to be shared by several other CCN proteins, is a unique essential feature which can no longer be ignored. Based on the structural and functional properties of CCN3, shared by most of the CCN family members, I propose an « all in one » concept in which CCN proteins are team members with specific functions that are aimed at the same goal. This model accounts both for the functional specificity of the various CCN proteins, their sequential and opposite or complementary effects in various biological context, and for the biological consequences of their physical interaction and biological cross-regulation.     

Cytokines in psoriasis

Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The disease is characterized by red, scaly and well-demarcated skin lesions formed by the hyperproliferation of epidermal keratinocytes. This hyperproliferation is driven by cytokines secreted by activated resident immune cells, an infiltrate of T cells, dendritic cells and cells of the innate immune system, as well as the keratinocytes themselves. Psoriasis has a strong hereditary character and has a complex genetic background. Genome-wide association studies have identified polymorphisms within or near a number of genes encoding cytokines, cytokine receptors or elements of their signal transduction pathways, further implicating these cytokines in the psoriasis pathomechanism. A considerable number of inflammatory cytokines have been shown to be elevated in lesional psoriasis skin, and the serum concentrations of a subset of these also correlate with psoriasis disease severity. The combined effects of the cytokines found in psoriasis lesions likely explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularization and skin inflammation. Thus, understanding which cytokines play a pivotal role in the disease process can suggest potential therapeutic targets. A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease. Here we review a number of key cytokines implicated in the pathogenesis of psoriasis.     

Cytokine therapies in HIV infection

The theoretical objectives of cytokine therapies in HIV infection are to impact T cell homeostasis and/or to improve immune functions or the mobilization of the HIV reservoir. Among cytokines, IL-2 and IL-7 are promising agents under clinical evaluation. Intermittent administration of IL-2 is by far the furthest studied strategy in HIV infection. This cytokine increases CD4 T lymphocytes in HIV-infected individuals. Recent clinical data showed that this effect is sustained over years. IL-2 therapy induces a peripheral expansion of T cells as a consequence of prolonged survival of T cells and decreased immune activation. These effects suggest that a cytokine therapy may interfere with critical factors of HIV disease. Recent data provide arguments that IL-2 therapy improves immune functions in HIV-infected patients. Whether these effects may be translated into clinical benefits is under evaluation in ongoing phase III studies. The potential interest of IL-7 in the treatment of HIV-infection is based on its crucial role on T cell homeostasis both in thymic output and peripheral T proliferation and survival. Although no data in human are still available, recent studies provide arguments to assess this cytokine in HIV infection. Phase I studies are ongoing or planned.     

Cytokine measurements in body fluids

Bioassays and immunoassays for cytokines are now widely available for use in clinical laboratories which may have little or no expertise in cytokine biology. Whilst this facilitates the accumulation of data concerning cytokine levels in body fluids in disease, it is based on the assumption that such assays can be used for this purpose. In many cases, the presence of complex interfering factors in plasma and other body fluids require that assays should be subjected to detailed assay validation before confidence can be placed on the results. It is the purpose of this report to outline the potential problems with cytokine assays and the criteria that should be applied before making measurements in biological fluids.     

Cytokine signaling exposed

In this issue, Lupardus et?al. (2011) provide images, obtained by electron microscopy, of a complete cytokine signaling complex, offering clues into the mechanism by which binding of cytokines to their cognate receptors triggers trans-phosphorylation and activation of Janus kinases.     

Cytokine disturbances in systemic lupus erythematosus

The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNFα, IFNα, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.     

Cytokine knockouts in contact hypersensitivity research

Contact hypersensitivity (CHS) is a Langerhans cell (LC)-dependent, T cell-mediated cutaneous immune response. CHS reflects a culmination of LC activities in vivo: uptake of epicutaneous antigens, migration into lymph nodes, and presentation of antigens to na?ve T cells. Although studies have suggested involvement of the cytokine network in LC migration and CHS initiation, the in vivo function of individual cytokines remains largely unknown. Gene targeting technology has made it possible to study in vivo functions of cytokines through gene-targeted knockout (KO) mice deficient in a given cytokine or its receptor. A variety of cytokine knockouts have been used to assign biological functions to specific cytokines in CHS. These studies have contributed significantly to our understanding of molecular mechanisms underlying CHS.     

Cytokine imbalance in non-immunological chronic disease

Over the last decade, cytokine imbalances have been associated with a plethora of diseases. While the Th(1)/Th(2) paradigm is widely used to explain the pathogenesis of immunological diseases, the role of cytokine imbalances for non-immunological diseases is still incompletely defined. The major obstacle here is to assess the extent to which non-immunological diseases are influenced by inflammation. Non-immunological diseases cover the whole spectrum from those triggered by infection-as may be the case for Alzheimer's disease-to those where the immune system has no apparent impact at all. Examples of the latter are bone diseases, including post-menopausal osteoporosis and skeletal malformations. In between there are diseases such as intrinsic asthma and osteoarthritis where the impact of the immune system is unclear. Thus far, imbalances affecting tumour necrosis factor (TNF)-alpha and members of the interleukin (IL)-1 and the TGF superfamily have been found in association with all of these diseases. We speculate here that cytokine imbalance will be found in additional diseases and touch on the role in phylogeny of cytokines outside the immune system.