Biology Reference
In-Depth Information
Cytokine synthesis is tightly controlled at the transcriptional level, but also
post-transcriptionally. In fact, many cytokine mRNAs contain adenosine
uridine (AU )-rich regions whose presence or removal strongly in¯uences their
half-lives and, ultimately, the levels of cytokine production (Revel and Groner,
1978). Conversely, cytokines profoundly a¨ect several cellular genes by in¯u-
encing both transcriptional and post-transcriptional events (Arai et al., 1990).
The biochemical pathways transducing cytokine signals to the nucleus have
been elucidated only recently. Many cytokines utilize the Janus kinases and
signal transducer and activator of transcription (JAK/STAT ) pathway. Acti-
vation and dimerization of di¨erent STATs is responsible for speci®c cytokine
e¨ects ( Ihle, 1995; Schindler and Darnell, 1995).
Cytokines are classi®ed as being either pro- or anti-in¯ammatory, or im-
munoregulatory if they exert di¨erential e¨ects on Th1 vs. Th2 cell polarization
(O'Garra and Murphy, 1996). Typical examples of pro-in¯ammatory cytokines
are tumor necrosis factor-a (TNF-a)orTNF-b (renamed lymphotoxin-a) and
interleukin-1a/b ( IL-1a/b), whereas transforming growth factor-b (TGF-b), IL-
4, and IL-10 are potent anti-in¯ammatory molecules. In addition, IL-4 induces
the di¨erentiation of and is secreted selectively by Th2 cells, devoted to the
humoral immune response. On the other hand, IL-12 and interferon-g ( IFN-g)
are the principal inducer and product of Th1 cells, respectively, leading to
phagocyte-dependent cell-mediated immune response. Both IL-12 and IFN-g
also exert pro-in¯ammatory e¨ects (O'Garra and Murphy, 1996; O'Garra et
al., 1997).
Cytokines are very important components of our immune defense against
pathogens and cancer cells; however, their dysregulated production can also
be involved in the pathogenesis of autoimmune diseases, such as rheumatoid
arthritis or autoimmune thyroiditis. In addition, genetic diseases leading to
primary immunode®ciencies frequently involve either cytokines or their recep-
tors (Jouanguy et al., 1999). On the other hand, cytokines or pharmacological
agents aimed at the suppression of their expression (such as cyclosporin A or
FK506) are experimentally used in di¨erent diseases, including human im-
munode®ciency virus (HIV ) disease, as discussed later, although still with great
di½culties caused by prominent side e¨ects (Chapuis et al., 2000).
Cytokines can be measured in all body ¯uids as well as in whole blood.
Enzyme-linked immunosorbent assay (ELISA) is the most common method
of detection of cytokines present in plasma, urine, and other secretions, or in
culture supernatants. Intracellular staining of cells maximally stimulated and
treated with inhibitors of secretion such as brefeldin-A allows the analysis
of cytokine expression by cyto¯uorimetry. By this approach, patterns of cyto-
kine expression can be interpolated with those of other cell-associated markers.
Cytokine detection has become an important tool for investigating major his-
tocompatibility complex (MHC)-restricted cytolytic T lymphocytes (CTL) ac-
tivities by the ELISPOT methodology. Finally, multiple molecular approaches,
from conventional to real-time polymerase chain reaction ampli®cation to RNase
protection assays, can be easily applied to study the expression patterns of sev-
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