Regulation of Cytokine Receptor Signaling by Nuclear Hormone Receptors: A New Paradigm for Receptor Interaction

Cytokine receptors act through a complex signaling network involving Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs) to regulate diverse biological processes controlling growth, development, homeostasis, and immune function. JAK/STAT signaling is terminated by negative regulators including the suppressors of cytokine signaling (SOCSs), protein tyrosine phosphatases, and protein inhibitors of activated STAT. There is a wealth of evidence that nuclear hormone receptors (NHRs) are important regulators of cytokine action. The molecular mechanisms underlying NHR regulation are incompletely understood, but may include control of cytokine production and modulation of the expression and signaling of cytokine receptors. NHRs regulate cytokine receptor signaling by affecting STAT expression and by acting as coregulators of STAT transcriptional action. More recently, NHRs have been shown to exert regulatory effects indirectly through SOCSs, which is a novel mechanism for receptor crosstalk. Better understanding of the regulatory interaction between these two classes of receptors potentially leads to new drug design and/or therapeutic strategies for treatment of cytokine-related diseases.