Chemokines constitute a family of chemoattractant cytokines and are subdivided into four families on the basis of the number and spacing of the conserved cysteine residues in the N-terminus of the protein. Chemokines play a major role in selectively recruiting monocytes, neutrophils, and lymphocytes, as well as in inducing chemotaxis through the activation of G-protein-coupled receptors. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. Both CCL2 and its receptor CCR2 have been demonstrated to be induced and involved in various diseases. Migration of monocytes from the blood stream across the vascular endothelium is required for routine immunological surveillance of tissues, as well as in response to inflammation. This review will discuss these biological processes and the structure and function of CCL2.

Monocyte chemoattractant protein-1 (MCP-1): an overview.

The TGF-β family comprises many structurally related differentiation factors that act through a heteromeric receptor complex at the cell surface and an intracellular signal transducing Smad complex. The receptor complex consists of two type II and two type I transmembrane serine/threonine kinases. Upon phosphorylation by the receptors, Smad complexes translocate into the nucleus, where they cooperate with sequence-specific transcription factors to regulate gene expression. The vertebrate genome encodes many ligands, fewer type II and type I receptors, and only a few Smads. In contrast to the perceived simplicity of the signal transduction mechanism with few Smads, the cellular responses to TGF-β ligands are complex and context dependent. This raises the question of how the specificity of the ligand-induced signaling is achieved. We review the molecular basis for the specificity and versatility of signaling by the many ligands through this conceptually simple signal transduction mechanism.

SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS

Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.

Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease

C-reactive protein (CRP) is an acute inflammatory protein that increases up to 1000-fold at sites of infection or inflammation. CRP is produced as a homo-pentameric protein, termed native CRP (nCRP), which can irreversibly dissociate at sites of inflammation and infection into five separate monomers, termed monomeric CRP (mCRP). CRP is synthesised primarily in liver hepatocytes but also by smooth muscle cells, macrophages, endothelial cells, lymphocytes and adipocytes. Evidence suggests estrogen in the form of hormone replacement therapy influences CRP levels in the elderly. Having been traditionally utilised as a marker of infection and cardiovascular events, there is now growing evidence that CRP plays important roles in inflammatory processes and host responses to infection including the complement pathway, apoptosis, phagocytosis, nitric oxide (NO) release and the production of cytokines, particularly interleukin-6 and tumour necrosis factor-alpha. Unlike more recent publications, the findings of early work on CRP can seem somewhat unclear and at times conflicting since it was often not specified which particular CRP isoform was measured or utilised in experiments and whether responses attributed to nCRP were in fact possibly due to dissociation into mCRP or lipopolysaccharide contamination. In addition, since antibodies for mCRP are not commercially available, few laboratories are able to conduct studies investigating the mCRP isoform. Despite these issues and the fact most CRP research to date has focussed on vascular disorders, there is mounting evidence that CRP isoforms have distinct biological properties, with nCRP often exhibiting more anti-inflammatory activities compared to mCRP. The nCRP isoform activates the classical complement pathway, induces phagocytosis and promotes apoptosis. On the other hand, mCRP promotes the chemotaxis and recruitment of circulating leukocytes to areas of inflammation and can delay apoptosis. The nCRP and mCRP isoforms work in opposing directions to inhibit and induce NO production respectively. In terms of pro-inflammatory cytokine production, mCRP increases interleukin-8 and monocyte chemoattractant protein-1 production whereas nCRP has no detectable effect on their levels. Further studies are needed to expand on these emerging findings and fully characterise the differential roles each CRP isoform at sites of local inflammation and infection.

/pdf/role-of-c-reactive-protein-at-sites-of-inflammation-and-2759rlw6ex.pdf

Role of C-Reactive Protein at Sites of Inflammation and Infection

Infiltration of macrophages in solid tumours is associated with poor prognosis and correlates with chemotherapy resistance in most cancers. In mouse models of cancer, macrophages promote cancer initiation and malignant progression by stimulating angiogenesis, increasing tumour cell migration, invasion and intravasation and suppressing antitumour immunity. At metastatic sites, macrophages promote tumour cell extravasation, survival and subsequent growth. Each of these pro-tumoural activities is promoted by a subpopulation of macrophages that express canonical markers but have unique transcriptional profiles, which makes tumour-associated macrophages (TAMs) good targets for anticancer therapy in humans through either their ablation or their re-differentiation away from pro-tumoural towards antitumoural states. In this Review, we evaluate the state of the art of TAM-targeting strategies, focusing on the limitations and potential side effects of the different therapies such as toxicity, rebound effects and compensatory mechanisms. We provide an extensive overview of the different types of therapy used in the clinic and their limitations in light of known macrophage biology and propose new strategies for targeting TAMs.

Targeting macrophages: therapeutic approaches in cancer.

Interplay of the HIV-1 regulatory protein, Tat, with several cellular factors plays an important role in transcriptional regulation of the viral promoter, the long terminal repeat (LTR). Special attention has been paid to NF-kappaB, a family of inducible transcription factors, which interact with a specific DNA motif within the LTR. Here, we report on the physical and functional interaction of NFBP, a recently identified protein that interacts with the P65 subunit of NF-kappaB, with HIV-1 Tat. NFBP colocalizes with Tat in the nucleus and nucleoli, recognizes the amino acid residues 37 to 48 of Tat, and its interaction is modulated by RNA molecules. The interaction of NFBP with Tat modulates the synergism between Tat and P65 in activating LTR transcription. In the absence of the kappaB-binding sites, NFBP augments the TAR-dependent activation by Tat, yet it interferes with the synergistic effect of P65 and Tat on LTR transcription.

Interplay between NFBP and NF-kappaB modulates tat activation of the LTR.

Infection with HIV-1 induces a variety of biological alterations to the host that are beneficial to the life cycle of the virus but may have adverse effects on the host cell Here we demonstrate that expression of Rad51, a major component of the homologous recombination-directed DNA repair (HRR) pathway, is induced upon HIV-1 infection of microglial cells Activation of Rad51 expression positively impacts on HIV-1 LTR transcription through a region of the viral promoter known for binding the inducible transcription factor NFκB Rad51 showed the ability to form a complex with the p65 subunit of NFκB and regulate the level of p65 interaction with LTR DNA encompassing the κB motif This study provides evidence for reciprocal interaction of HIV-1 and a host DNA repair protein that impacts on expression of the viral genome These results also point to the ability of HIV-1 to recruit proteins involved in DNA repair that are necessary for retroviral DNA integration, efficient replication and prevention of viral-induced cell death

Activation of HIV-1 LTR by Rad51 in microglial cells.

To ensure successful replication, HIV-1 has developed a Rev-mediated RNA transport system that promotes the export of unspliced genomic RNA from nuclei to cytoplasm. This process requires the Rev responsive element (RRE) that is positioned in the viral transcript encoding Env protein, as well as in unspliced and singly spliced viral transcripts. We identified Purα, a single-stranded nucleic acid binding protein as a cellular partner for Rev that augments the appearance of unspliced viral RNAs in the cytoplasm. A decrease in the level of Purα expression by siRNA diminishes the level of Rev-dependent expression of viral RNA. Through its nucleic acid binding domain, Purα exhibits the ability to interact with the multimerization and RBD domains of Rev. Similar to Rev, Purα associates with RRE and in the presence of Rev forms a complex with slower electrophoretic mobility than those from Rev:RRE and Purα:RRE. The interaction of Purα with RRE occurs in the cytoplasm where enhanced association of Rev with RRE is observed. Our data indicate that the partnership of Purα with Rev is beneficial for Rev-mediated expression of the HIV-1 genome.

/pdf/pura-as-a-cellular-co-factor-of-rev-rre-mediated-expression-19i2llp3nw.pdf

Purα as a cellular co‐factor of Rev/RRE‐mediated expression of HIV‐1 intron‐containing mRNA

MH2 domain of Smad3 reduces HIV-1 Tat-induction of cytokine secretion.

Increased life expectancy and the need for long-term antiretroviral therapy have brought new challenges to the clinical management of HIV-infected individuals. The prevalence of osteoporosis and fractures is increased in HIV-infected patients; thus optimal strategies for risk management and treatment in this group of patients need to be defined. Prevention of bone loss is an important component of HIV care as the HIV population grows older. Understanding the mechanisms by which HIV infection affects bone biology leading to osteoporosis is crucial to delineate potential adjuvant treatments. This review focuses on HIV-induced osteoporosis within the context of microRNAs (miRNAs) by reviewing first basic concepts of bone biology as well as current knowledge of the role of miRNAs in bone development. Evidence that HIV-associated osteoporosis is in part independent of therapies employed to treat HIV (HAART) is supported by cross-sectional and longitudinal studies and is the focus of this review.

/pdf/hiv-and-bone-disease-a-perspective-of-the-role-of-micrornas-3qp99tgimp.pdf

Bassel E. Sawaya

Papers

Interplay between NFBP and NF-kappaB modulates tat activation of the LTR.

Activation of HIV-1 LTR by Rad51 in microglial cells.

Purα as a cellular co‐factor of Rev/RRE‐mediated expression of HIV‐1 intron‐containing mRNA

MH2 domain of Smad3 reduces HIV-1 Tat-induction of cytokine secretion.

HIV and Bone Disease: A Perspective of the Role of microRNAs in Bone Biology upon HIV Infection.