Begell House Inc.
Critical Reviews™ in Immunology
CRI
1040-8401
22
3
2002
Cytokine Responses to Physical Activity, with Particular Reference to IL-6: Sources, Actions, and Clinical Implications
18
10.1615/CritRevImmunol.v22.i3.10
The present review examines the cytokine response to acute exercise stress, with particular emphasis on the balance between proinflammatory and anti-inflammatory mechanisms, and the release of IL-6. Prolonged endurance exercise induces a sequenced release of pro- and anti-inflammatory cytokines, and IL-6 plays a dominant role. The magnitude of this response bears a general relationship to the intensity of effort, but the duration of activity and many environmental factors also modulate cytokine release. Although many types of cells are capable of producing cytokines, the main source of the exercise-induced IL-6 production appears to be the exercising muscle. The primary function of the additional IL-6 may be to regulate the supply of carbohydrate as muscle reserves of glycogen become depleted. There is also a delayed release of cytokines following eccentric exercise that is related to the repair of muscle injury. Since the production of cytokines is greater with endurance than with resistance exercise, it seems unlikely that they play an important role in the hypertrophy of muscle and bone. More research is needed on a number of important clinical issues where the exercise-induced release of cytokines may have relevance. Exercise-induced cytokine secretion has the potential to provide a simple model of sepsis. Preliminary observations suggest it may also modulate the risk of type 2 diabetes mellitus. Cytokine concentrations are increased in chronic fatigue syndrome, although it is less clear that the cytokine secretion is responsible for fatigue in humans. Exercise-induced modulations in cytokine secretion may contribute to allergies, bronchospasm, and upper respiratory infections in the endurance athlete. Further, the cytokine cascade is involved in the process of atherogenesis, and exercise-induced changes in cytokine production may expose latent HIV to chemotherapeutic agents.
DNA Target Motifs of Somatic Mutagenesis in Antibody Genes
18
10.1615/CritRevImmunol.v22.i3.20
Gary S.
Shapiro
Department of Immunology, National Jewish Medical and Research Center and University of Colorado School of Medicine, Denver, CO 80206
Lawrence J.
Wysocki
Department of Immunology, National Jewish Medical and Research Center and University of Colorado School of Medicine, Denver, CO 80206
During humoral immunity to T-cell-dependent antigens, responding В lymphocytes selectively mutate their antibody variable region genes at a high rate. This, together with the process of clonal selection, ultimately enhances the affinity and specificity of the antibody molecule and memory В cells that express it as a receptor. Despite several decades of investigation, the mutation mechanism has remained unresolved, largely due to the convoluted nature of experimental systems used to approach it. Somatic mutations preferentially occur within specific oligonucleotide motifs, and this targeting is consistent in all immunoglobulin genes of humans and mice that we have examined, suggesting that a conserved mechanism operates in both species. Our mutation targeting analyses implicate evolution of germline variable gene sequences to direct somatic mutations to specific codon positions in a manner that regulates the frequency of amino acid replacements to the benefit of the antibody product. Finally, our recent strand bias analyses support the idea that somatic mutation occurs preferentially, perhaps exclusively, at two bases on both strands of DNA. These and related observations from other laboratories support a mutation model that invokes at least two error-prone polymerases that have distinct template biases and requirements for elements of postreplicative mismatch repair.
Immune Function of the Decoy Receptor Osteoprotegerin
15
10.1615/CritRevImmunol.v22.i3.30
Asa K.
Bengtsson
Department of Microbiology, Department of Immunology, University of Washington, Box. 357 330, Seattle, WA 98195
Elizabeth J.
Ryan
Department of Microbiology, Regional Primate Research Center, University of Washington, Box. 357 330, Seattle, WA 98195
Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor (TNFR) superfamily. OPG has an important function as a protector of bone, demonstrated by the fact that OPG(-/-) mice have severe osteoporosis. OPG acts as a decoy receptor, binding to RANK ligand (RANKL), thus preventing the interaction between receptor activator of NF-κB (RANK) and RANKL. This interaction is required for the development of functionally active osteoclasts. Osteoclasts are cells of the monocytic lineage that are responsible for bone resportion. Furthermore, as well as being an important player in the regulation of bone metabolism, OPG also has a role in the regulation of the immune response. Dendritic cells (DCs) express RANK and T cells express RANKL. The ligation of RANK by RANKL can activate both T cells and DCs. Furthermore, both B cells and DCs secrete OPG, and this secretion is regulated by the CD40 receptor. -OPG(-/-) mice have B-cell developmental defects. Also, DCs isolated from OPG(-/-) mice more efficiently present antigen in vitro and secrete elevated amounts of inflammatory cytokines when stimulated with bacterial products, or soluble RANKL in vitro. Taken together, this suggests that OPG plays an important role in the immune response regulating the interactions between T cells and DCs.
Signal Integration Following Toll-like Receptor Triggering
34
10.1615/CritRevImmunol.v22.i3.40
Alexander
Dalpke
Institute of Medical Microbiology and Hygiene, University of Marburg, Germany
Klaus
Heeg
Institute of Medical Microbiology and Hygiene, University of Marburg, Germany
Innate immune cells sense infectious danger through recognition of pathogen-associated molecular patterns (PAMP). Toll-like receptors (TLRs) play a pivotal role in the recognition of PAMP. Although various TLRs with distinct ligand specificities are expressed almost completely and contemporaneously by innate immune cells, and although central key signal transduction pathways of TLRs are shared, the innate response pattern is not uniform. Innate immune cells organize their response dependent on spatial and temporal requirements and mount a pathogen-specific and microbial-adopted reaction. Thus, after triggering of TLRs, complex signaling interactions take place that control and shape the reactivity patterns of innate immune cells. Here we discuss the central signaling pathways of TLRs and their interconnection with other signaling pathways, with emphasis on Janus kinases/signal transducers and activators of transcription (JAK/STAT)-dependent intracellular signals. Cis and trans acting signal convergence mechanisms and mutual influence of TLR and cytokine signaling pathways determine the response profile. Hence, in innate immune cells, integration and processing of microbial-dependent and immunologic signals is achieved within individual cells to ascertain an appropriate immune response. Knowledge of these complex mechanisms will help to clarify the critical events during initiation of infection, which in turn may lead to new strategies to control and overcome infectious disease.