Biology Reference
In-Depth Information
6
Circadian Organization of the
Immune Response: Rat Adjuvant
Arthritis as a Model
Ana Isabel Esquifino
1
, Daniel P. Cardinali
2
1
Departamento de Bioquímica y Biología Molecular III, Facultad
de Medicina, Universidad Complutense, Madrid, Spain,
2
Departamento
de Docencia a Investigación, Facultad de Ciencias Médicas, Pontificia
Universidad Católica Argentina, Buenos Aires, Argentina
6.1 The Circadian Clock Has Indispensable
Biological Functions
Organisms populating the Earth are under the steady influence of daily and seasonal
changes resulting from the planet's rotation and orbit around the sun. This periodic
pattern is most prominently manifested by the light-dark cycle and has led to the
establishment of endogenous circadian timing systems that synchronize biological
functions to the environment. This is the basis of predictive homeostasis
[1]
, which
evolved as an adaptation to anticipate predictable changes in the environment, such
as light and darkness, temperature, food availability, or predator activity. Therefore,
the circadian clock is one of the most indispensable biological functions for living
organisms, because it acts as a multifunctional timer to adjust the homeostatic sys-
tem, including sleep and wakefulness, immune function, hormonal secretions, and
various other bodily functions, to the 24-hour cycle
[2-4]
.
In mammals, the circadian system is composed of many individual, tissue-
specific cellular clocks. To generate coherent physiological and behavioral responses,
the phases of this multitude of cellular clocks are orchestrated by a master circadian
pacemaker residing in the suprachiasmatic nuclei (SCN) of the hypothalamus. At a
molecular level, circadian clocks are based on clock genes, some of which encode
proteins able to feed back and inhibit their own transcription. These cellular oscilla-
tors consist of interlocked transcriptional and posttranslational feedback loops that
involve a small number of core clock genes (about 12 genes identified currently).
The positive drive of the daily clock consists of two basic helix-loop-helix, PAS-
domain-containing transcription factor genes, called Clock and Bmal1. The protein
products of these genes form heterodimeric complexes that control the transcrip-
tion of other clock genes, notably three Period (Per1/Per2/Per3) genes and two
