Expression of IL-20 in synovium and lesional skin of patients with psoriatic arthritis: differential response to alefacept treatment

Introduction

Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T-cell activation) has been shown to result in improvement in psoriasis but has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key proinflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown.

Methods

Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open-label study. Skin biopsies were taken before and after 1 and 6 weeks, whereas synovial biopsies were obtained before and 4 and 12 weeks after treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n = 10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated with digital image analysis. Double staining was performed with IL-20 and CD68 (macrophages), and conversely with CD55 (fibroblast-like synoviocytes, FLSs) to determine the phenotype of IL-20-positive cells in PsA synovium. IL-20 expression in skin sections (n = 6) was analyzed semiquantitatively.

Results

IL-20 was abundantly expressed in both PsA and RA synovial tissues. In inflamed PsA synovium, CD68⁺ macrophages and CD55⁺ FLSs coexpressed IL-20, and its expression correlated with the numbers of FLSs. IL-20 expression in lesional skin of PsA patients decreased significantly (P = 0.04) 6 weeks after treatment and correlated positively with the Psoriasis Area and Severity Index (PASI). IL-20 expression in PsA synovium was not affected by alefacept.

Conclusions

Conceivably, the relatively limited effectiveness of alefacept in PsA patients (compared with anti-tumor necrosis factor (TNF) therapy) might be explained in part by persistent FLS-derived IL-20 expression.     

Phylogenetic inference under the pure drift model

When pairwise genetic distances are used for phylogenetic reconstruction, it is usually assumed that the genetic distance between two taxa contains information about the time after the two taxa diverged. As a result, upon an appropriate transformation if necessary, the distance usually can be fitted to a linear model such that it is expressed as the sum of lengths of all branches that connect the two taxa in a given phylogeny. This kind of distance is referred to as "additive distance." For a phylogenetic tree exclusively driven by random genetic drift, genetic distances related to coancestry coefficients (theta XY) between any two taxa are more suitable. However, these distances are fundamentally different from the additive distance in that coancestry does not contain any information about the time after two taxa split from a common ancestral population; instead, it reflects the time before the two taxa diverged. In other words, the magnitude of theta XY provides information about how long the two taxa share the same evolutionary pathways. The fundamental difference between the two kinds of distances has led to a different algorithm of evaluating phylogenetic trees when theta XY and related distance measures are used. Here we present the new algorithm using the ordinary- least-squares approach but fitting to a different linear model. This treatment allows genetic variation within a taxon to be included in the model. Monte Carlo simulation for a rooted phylogeny of four taxa has verified the efficacy and consistency of the new method. Application of the method to human population was demonstrated.      

Compensatory evolution for a gene deletion is not limited to its immediate functional network

Background  

Genetic disruption of an important phenotype should favor compensatory mutations that restore the phenotype. If the genetic basis of the phenotype is modular, with a network of interacting genes whose functions are specific to that phenotype, compensatory mutations are expected among the genes of the affected network. This perspective was tested in the bacteriophage T3 using a genome deleted of its DNA ligase gene, disrupting DNA metabolism.     

Phylogenetic evidence for role-reversals of gender-associated mitochondrial DNA in Mytilus (Bivalvia: Mytilidae)

Distinct gender-associated mitochondrial DNA (mtDNA) lineages (i.e., lineages which are transmitted either through males or through females) have been demonstrated in two families of bivalves, the Mytilidae (marine mussels) and the Unionidae (freshwater mussels), which have been separated for more than 400 Myr. The mode of transmission of these M (for male-transmitted) and F (for female-transmitted) molecules has been referred to as doubly uniparental inheritance (DUI), in contrast to standard maternal inheritance (SMI), which is the norm in animals. A previous study suggested that at least three origins of DUI are required to explain the phylogenetic pattern of M and F lineages in freshwater and marine mussels. Here we present phylogenetic evidence based on partial sequences of the cytochrome c oxidase subunit I gene and the 16S RNA gene that indicates the DUI is a dynamic phenomenon. Specifically, we demonstrate that F lineages in three species of Mytilus mussels, M. edulis, M. trossulus, and M. californianus, have spawned separate lineages which are now associated only with males. This process is referred to as "masculinization" of F mtDNA. By extension, we propose that DUI may be a primitive bivalve character and that periodic masculinization events combined with extinction of previously existing M types effectively reset the time of divergence between conspecific gender-associated mtDNA lineages.      

Cyclic hydrostatic compression stimulates chondroinduction of C3H/10T1/2 cells

While the potential for intermittent hydrostatic pressure to promote cartilaginous matrix synthesis is well established, its potential to influence chondroinduction remains poorly understood. This study examined the effects of relatively short- and long-duration cyclic hydrostatic compression on the chondroinduction of C3H/10T1/2 murine embryonic fibroblasts by recombinant human bone morphogenetic protein-2 (rhBMP-2). Cells were seeded at high density into round bottom wells of a 96-well plate and supplemented with 25 ng/ml rhBMP-2. Experimental cultures were subjected to either 1,800 cycles/day or 7,200 cycles/day of 1 Hz sinusoidal hydrostatic compression to 5 MPa (applied 10 min on/10 min off) for 3 days. Non-pressurized control and experimental cultures were maintained in static culture for an additional 5 days. Cultures were then analyzed for alcian blue staining intensity, DNA and sulfated glycosaminoglycan (sGAG) content, and for the rate of collagen synthesis. Whereas cultures subjected to 1,800 pressure cycles exhibited no significant differences (statistical or qualitative) compared to controls, those subjected to 7,200 cycles stained more intensely with alcian blue, contained nearly twice as much sGAG, and displayed twice the rate of collagen synthesis as non-pressurized controls. This study demonstrates the potential for cyclic hydrostatic compression to stimulate chondrogenic differentiation of the C3H/10T1/2 cell line in a duration-dependent manner.     

NAD metabolism in aging and cancer

NAD⁺ and its derivatives NADH, NADP⁺, and NADPH are essential cofactors in redox reactions and electron transport pathways. NAD serves also as substrate for an extensive series of regulatory enzymes including cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases which are O-acetyl-ADP-ribosyltransferases. As a result of the numerous and diverse enzymes that utilize NAD as well as depend on its synthesis and concentration, significant interest has developed in its role in a variety of physiologic and pathologic processes, and therapeutic initiatives have focused both on augmenting its levels as well as inhibiting some of its pathways. In this article, we examine the biosynthesis of NAD, metabolic processes in which it is involved, and its role in aging, cancer, and other age-associated comorbidities including neurodegenerative, cardiovascular, and metabolic disorders. Therapeutic interventions to augment and/or inhibit these processes are also discussed.Impact statementNAD is a central metabolite connecting energy balance and organismal growth with genomic integrity and function. It is involved in the development of malignancy and has a regulatory role in the aging process. These processes are mediated by a diverse series of enzymes whose common focus is either NAD’s biosynthesis or its utilization as a redox cofactor or enzyme substrate. These enzymes include dehydrogenases, cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases. This article describes the manifold pathways that comprise NAD metabolism and promotes an increased awareness of how perturbations in these systems may be important in disease prevention and/or progression.