The functions of cytokines and their uses in toxicology.
Cytokines are critical controllers of cell, and hence tissue, growth, migration, development and differentiation. The family includes the inflammatory cytokines such as the interleukins and interferons, growth factors such as epidermal and hepatocyte growth factor and chemokines such as the macrophage inflammatory proteins, MIP-1alpha and MIP-1beta. They do not include the peptide and steroid hormones of the endocrine system. Cytokines have important roles in chemically induced tissue damage repair, in cancer development and progression, in the control of cell replication and apoptosis, and in the modulation of immune reactions such as sensitization. They have the potential for being sensitive markers of chemically induced perturbations in function but from a toxicological point of view, the detection of cytokine changes in the whole animal is limited by the fact that they are locally released, with plasma measures being generally unreliable or irrelevant, and they have short half lives which require precise timing to detect. Even where methodology is adequate the interpretation of the downstream effects of high, local concentrations of a particular cytokine is problematic because of their interdependence and the pleiotropism of their action. A range of techniques exist for their measurement including those dependent upon antibodies specific for the respective cytokines, but with the introduction of genomic and proteomic technology, a more complete study of cytokine changes occurring under the influence of chemical toxicity should be possible. Their further study, as markers of chemical toxicity, will undoubtedly lead to a greater understanding of how synthetic molecules perturb normal cell biology and if, and how, this can be avoided by more intuitive molecular design in the future.
Foster
J R
JR
Safety Assessment, AstraZeneca plc, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. John-Foster@astrazeneca.com
D000818:Animals; D017209:Apoptosis; D001681:Biological Assay / Q000379:methods; D015415:Biomarkers; D002454:Cell Differentiation; D002455:Cell Division; D016207:Cytokines / Q000032:analysis / Q000502:physiology* / Q000627:therapeutic use; D004342:Drug Hypersensitivity / Q000175:diagnosis* / Q000378:metabolism; D004586:Electrophoresis; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008264:Macrophages / Q000502:physiology; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D011863:Radioimmunoassay / Q000379:methods
D015415:Biomarkers; D016207:Cytokines