Abstract:
Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal
transducers and activators of transcription (STATs) (STAT1, STAT2,
STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of
more than 50 cytokines and growth factors in many different cell types.
Located intracellularly and downstream of cytokine receptors, JAKs
integrate and balance the actions of various signaling pathways. With
distinct panels of STAT-sensitive genes in different tissues, this
highly heterogeneous system has broad in vivo functions playing a
crucial role in the immune system. Thus, the JAK/STAT pathway is
critical for resisting infection, maintaining immune tolerance, and
enforcing barrier functions and immune surveillance against cancer.
Breakdowns of this system and/or increased signal transduction may lead
to autoimmunity and other diseases. Accordingly, the recent development
and approval of the first small synthetic molecules targeting JAK
molecules have opened new therapeutic avenues of potentially broad
therapeutic relevance. Extensive data are now available regarding the
JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines
is also a hallmark of systemic lupus erythematosus (SLE), and targeting
the JAK/STAT proteins allows simultaneous suppression of multiple
cytokines. Evidence from in vitro studies and animal models supports a
pivotal role also in the pathogenesis of cutaneous lupus and SLE. This
has important therapeutic implications, given the current paucity of
targeted therapies especially in the latter. Herein, we summarize the
currently available literature in experimental SLE, which has led to the
recent promising Phase II clinical trial of a JAK inhibitor.
Authors:
Alunno, Alessia
Padjen, Ivan
Fanouriakis, Antonis
Boumpas,
Dimitrios T.
