TABLE 2

Mechanisms of CB₁R and CB₂R regulation in disease

Disease/System	Mechanism	Cell Type/ Animal Model	Implications
Liver steatosis	RAR-γ binds the −500 to +50 region of the CB₁R promoter and increases its expression (Mukhopadhyay et al., 2010).	Primary cultured mouse hepatocytes	Retinoic acid released from hepatic stellate cells induces CB₁R expression in hepatocytes, which in turn induces lipogenesis (Jeong et al., 2008).
Inflammation	Cannabinoids induce CB₁R mRNA expression in T cells by an IL-4- and CB₂R-dependent mechanism (Borner et al., 2007).	Jurkat T cells	CB₁R is expressed at very low levels in resting T cells; when induced, it seems to have anti-inflammatory effects (Molina-Holgado et al., 2003; Nakajima et al., 2006). These studies together suggest a feedback mechanism in T cells whereby cannabinoids induce expression of anti-inflammatory IL-4 via CB₂R, and IL-4 in turn increases CB₁R transcription (Borner et al., 2008).
	IL-4 directly increases CB₁R mRNA expression in T cells via STAT6 binding to a STAT6 element at nt −2769 upstream from human exon1 TSS (Borner et al., 2008).	Primary human T cells and Jurkat T cells
	IFNγ and GM-CSF synergize to increase CB₂R mRNA expression in microglia (Maresz et al., 2005).	Primary cultured mouse microglial cells	Increases in proinflammatory IFNγ and GM-CSF could mediate the increased microglial expression of CB₂R seen in EAE model of MS (Maresz et al., 2005).
Neuropathic Pain	CB₁R protein up-regulation in the spinal cord is mediated by Trk and MAPK (Lim et al., 2003) and GR (Wang et al., 2007).	Rat chronic constriction injury model of neuropathic pain	Neurotrophic factors and corticosteroids released with nerve injury may mediate CB₁R up-regulation via the Trk/MAPK pathway and GR, respectively (Lim et al., 2003; Wang et al., 2007).
Cancer	Increased DNA methylation of CB₁R promoter leads to decreased expression of CB₁R (Wang et al., 2008).	Human colorectal cancer cells	Loss of CB₁R expression leads to enhanced tumor proliferation in a mouse model of colorectal cancer (Wang et al., 2008); first evidence of a role for epigenetics in CB₁R regulation.
Feeding behaviors and energy homeostasis	CNS-specific knockout of SF-1 leads to loss of CB₁R expression in the ventromedial hypothalamus. SF-1 directly increases CB₁R expression via SF-1 element at nt −101 within the mouse promoter (Kim et al., 2008).	CNS-specific SF-1 knockout mouse and various cell lines	CNS-specific SF-1 knockouts do not show the appetite-stimulating effects of CB₁R agonists. SF-1 regulation of CB₁R expression in the VMH is thus required for cannabinoid effects on food intake (Kim et al., 2008).
Neurodegenerative	Decreased striatal CB₁R levels in HD are due to decreased transcription (McCaw et al., 2004).	Mouse HD model	Striatal CB₁R modulates dopamine transmission, which is dysregulated in HD (see refs within McCaw et al., 2004).

RAR-γ, retinoic acid receptor-γ; IL, interleukin; STAT, signal transducer and activator of transcription; TSS, transcription start site; IFN, interferon; GM-CSF, granulocyte-macrophage–colony-stimulating factor; EAE, experimental autoimmune encephalitis; MS, multiple sclerosis; CNS, central nervous system; SF-1, steroidogenic factor-1; nt, nucleotide(s); HD, Huntington's disease.