Biological signals最新文献

Recent clinical and experimental evidence indicates that many of the sequelae of hemolytic transfusion reactions may be mediated by cytokines, including interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, the chemokines interleukin-8 and monocyte chemoattractant protein-1, and interleukin-1 receptor antagonist. Experimental models of both acute and delayed hemolytic transfusion reactions demonstrate the production of these molecules. The time course and relative patterns of production correlate well with known clinical manifestations of these reactions. Tumor necrosis factor-alpha appears to be central to ABO incompatibility reactions, and stimulates endothelial cells to exhibit procoagulant activity and surface adhesion molecules.

In rodents, bleomycin administration results in a route-, dose- and strain-dependent pulmonary inflammatory response. Given intratracheally, this response is characterized by increases in leukocyte accumulation, fibroblast proliferation, and collagen content. We believe that characterization of the cell types and soluble mediators present in the lesion will lend significant insight into the processes modulating pulmonary fibrosis. Recent studies have identified monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) as mediators of the inflammatory response in the lungs of human patients afflicted with idiopathic pulmonary fibrosis. Based on this compelling evidence for the involvement of C-C chemokines in fibrotic pathologies, we investigated the roles of MIP-1 alpha and MCP-1 protein in bleomycin-induced lung injury. In this study, we have established that neutralization of MIP-1 alpha and MCP-1 significantly reduces inflammatory cell accumulation. Further, we have shown that passive immunotherapy with either anti-MCP-1 or anti-MIP-1 alpha antibodies significantly reduced mononuclear phagocyte accumulation in bleomycin-challenged mice. These experiments strongly support the hypothesis that MIP-1 alpha and MCP-1 contribute to the recruitment of leukocytes during the pulmonary inflammatory response to bleomycin challenge.

Allergic airway inflammation is characterized by peribronchial eosinophil accumulation within the submucosa surrounding the airways. The development of appropriate animal models to dissect the critical mechanisms involved in the deleterious responses is crucial for the development of proper therapeutic approaches. We have utilized a model of allergic airway inflammation induced by intratracheal challenge with parasite (Schistosoma mansoni) egg antigen in presensitized mice. The use of this model to examine the eosinophil recruitment has identified key cytokines involved in the responses. These cytokines include interleukin-4 and tumor necrosis factor, which appear to act as early response mediators as well as C-C chemokines macrophage inflammatory protein-1 alpha and RANTES, which act directly on eosinophil recruitment.

The recruitment of various leukocyte populations to an area of injured and inflamed tissue is one of the most fundamental host defense responses. Historic evidence supports the concept that the pathology of acute inflammation is characterized by the elicitation of neutrophils, while the leukocyte composition of more chronic inflammatory responses is mononuclear in nature. Interestingly, little is known regarding the mechanism involved in the "switch' from an acute neutrophil-mediated response to a chronic mononuclear-cell-directed immune reaction. Recent studies demonstrate that two supergene families of chemokines play a key role in dictating the recruitment of specific leukocyte populations necessary for the appropriate inflammatory response. The expression of specific chemokines appears to be under the control of other cytokines, such as interleukins-1, -4 and -10, and tumor necrosis factor, that serve as either positive or negative regulatory mediators in the control of chemokine production, thus, controlling the recruitment of leukocyte subpopulations.

Effective host defense against bacterial invasion is characterized by the vigorous recruitment and activation of inflammatory cells, which are dependent upon the coordinated expression of both pro- and anti-inflammatory cytokines. In this study, we have demonstrated that both C-X-C and C-C chemokines are integral components of antibacterial host defense. Specifically, studies in vitro indicate that macrophage inflammatory protein-2 (MIP-2) and MIP-1 alpha augment the ability of PMN and alveolar macrophages, respectively, to phagocytose and kill Escherichia coli. In addition, MIP-2 and MIP-1 alpha are expressed within the lung in response to the intratracheal instillation of Klebsiella pneumoniae, and the inhibition of MIP-2 bioactivity in vivo results in decreases in lung PMN influx, bacterial clearance, and early survival. Finally, the anti-inflammatory cytokine interleukin-10 (IL-10) is also expressed within the lung during the evolution of Klebsiella pneumonia, and neutralization of IL-10 results in enhanced proinflammatory cytokine production, bacterial clearance, and increases in both short- and long-term survival. In conclusion, our studies indicate that specific chemokines are important mediators of leukocyte recruitment and/or activation in bacterial pneumonia, and that the expression of these chemokines is regulated by endogenously produced IL-10.

Human diploid fibroblasts (HDFs) undergo a limited number of population doublings in vitro and are widely used as a model of cellular aging. Despite growing evidence that cellular aging occurs as a result of altered gene expression, little is known about the activity of transcription factors that regulate gene expression in aging cells. Here we survey the relevant literature regarding altered gene expression and the role of transcription factors during cellular aging, focusing upon the serum response factor (SRF). SRF is hyperphosphorylated in senescent HDFs and fails to bind to the serum-response element in the c-fos promoter. Differential phosphorylation during replicative aging may contribute, at least in part, to the altered activity of SRF and possibly other transcription factors and to subsequent changes in the expression of serum-regulated genes in senescent HDFs.

This review develops the concept of p53 as a transcription factor mediating growth arrest or cell death in response to long-term (senescence-related) as well as acute (DNA damage) signals. Evidence is presented to support the importance of both functions in tumour development. The role of p53 in senescence is discussed in the context of the telomere theory and in relation to its more established function as a 'guardian of the genome'. Finally, data indicating important tissue-specific differences in the control of proliferative life-span by p53 are reviewed, together with potential clinical implications.

Normal somatic cells invariably enter a state of permanent growth arrest and altered function after a finite number of divisions. This phenomenon is termed cellular or replicative senescence. Replicative senescence is thought to be a tumor-suppressive mechanism, and a contributing factor in aging. Three features distinguish senescent from presenescent cells: an irreversible block to cell proliferation, increased resistance to apoptotic death, and changes in differentiated functions. Senescence entails an altered pattern of gene expression, much of which is due to altered transcription. At least three growth regulatory transcriptional modulators are repressed in senescent cells: the c-fos component of the AP1 transcription factor, the Id1 and Id2 helix-loop-helix (HLH) proteins that negatively regulate basic HLH transcription factors, and the E2F-1 component of the E2F transcription factor. Failure to express any one of these modulators is very likely sufficient to arrest cell proliferation. Loss of these modulators may also explain many of the functional changes shown by senescent cells. In the case of c-fos repression, the resulting decline in AP-1 activity may be exacerbated by an altered ratio of AP-1 components to a protein known as QM or Jif. QM interacts with the c-jun component of AP-1 and suppresses AP-1 activity. We cloned QM from a senescent fibroblast cDNA library, and found that it was neither cell cycle- nor senescence-regulated. However, QM suppressed the growth of murine and human fibroblasts when overexpressed. Thus, an altered balance between positive factors (e.g., AP-1 components) and negative factors (e.g., QM) may lead to the growth arrest, as well as the changes in differentiated gene expression, that are a hallmark of senescent cells.

Androgen receptor (AR) is a ligand-activated transcription factor involved in mediating male reproductive functions. The high expression of the AR gene in target tissues of young-adult animals is generally followed by an age-dependent decline during the postreproductive life. The liver of male rats shows about a 50- to 100-fold decline in androgen sensitivity during old age due to a concomitant decline of the AR gene expression. This decline corresponds to changes in the nuclear level of several transcription factors that bind to the AR gene promoter. The positively acting factors that control the AR gene and undergo an age-dependent decline include the age-dependent transcription factor (ADF), Sp1 and the serum response factor (SRF). Nuclear factor kappa B, which functions as a negative regulator of the AR promoter, undergoes about a 10-fold increase during the age-dependent loss of the hepatic androgen sensitivity. Additionally, AP3, which can potentially function as a regulator of the AR gene, shows a marked increase during old age. Thus, a coordinated interaction among a number of positive and negative regulators appears to guide the downregulation of the AR gene during aging.