The Cannabinoid System and Cytokine Network

Abstract

Many advances have been made in the last few years concerning our understanding of the receptors and ligands composing the cannabinoid system. Likewise, the science surrounding cytokine biology has advanced enabling us to measure these proteins more precisely as well as understand and interpret the meaning of changes in their levels. Scientists wishing to study the health consequences of smoking marijuana as well as understand the possible role of endogenous cannabimimetic ligands in immune regulation have continued to study the influence of these substances on the regulation and development of the cytokine network. Research has shown that two major cannabinoid receptor subtypes exist and that subtype 1 (CB1) is expressed primarily in the brain whereas subtype 2 (CB2) is expressed primarily in the periphery. A variety of ligands for these receptors based on the cannabinoid structure have been synthesized and studied as well as low affinity compounds, noncannabinoid ligands, and endogenous ligands derived from fatty acid eicosanoids. Highly selective receptor antagonists have also been introduced and studied. Synthetic, low affinity ligands such as (+)-HU-211 and DMH-11C have been shown to cause anti-inflammatory effects possibly through inhibiting the production and action of TNF-alpha and other acute phase cytokines. In addition, suppression of TNF and other cytokines such as GM-CSF, IL-6, IFNgamma, and IL-12 has also been seen following exposure to high affinity and psychoactive ligands such as marijuana and THC. However, some of these ligands have also been shown to increase rather than decrease interleukins such as IL-1, IL-4, IL-10, and IL-6, cytokines such as TNF-alpha, and chemokines such as IL-8, MIP-1, and RANTES. The endogenous ligand, anandamide, has been shown in culture to either suppress the proliferation response to prolactin or enhance the response to cytokines such as IL-3 and IL-6. This eicosanoid has also been shown to increase the production of interleukins and other cytokines. Cannabinoid receptors have been shown to be involved in some but not all of these effects. It is clear that psychoactive and nonpsychoactive compounds have demonstrated effects in vivo and in vitro on the production and function of a variety of cytokines. Depending upon the model system, these effects are often conflicting, and the involvement of cannabinoid receptors is unclear. However, enough evidence exists to suggest that the cannabinoid system significantly impacts the functioning of the cytokine network, and this association may provide clues to the mechanisms of certain immune diseases and form the basis for new immunotherapies.

Does megestrol acetate down-regulate interleukin-6 in patients with cancer-associated anorexia and weight loss? A North Central Cancer Treatment Group investigation

“…As noted earlier, the effects of cannabinoids on IL-6 have not been well studied, but there are several reports that do not suggest they down-regulate this cytokine [4,11]. The other two studies cited earlier included either a baseline comparison or a comparison with a control group of non-cancer patients.…”

“…This clinical trial examined the orexigenic effects of megestrol acetate, the cannabinoid dronabinol, versus the combination of both for the treatment of cancer-associated anorexia and weight loss (work submitted) and found that megestrol acetate was superior to dronabinol in its orexigenic effects in the doses prescribed. It should be noted that a few previous studies have examined the effect of cannabinoids on IL-6 and that overall these studies suggest these agents do not down-regulate this cytokine [4,11]. The goals of the translational component reported here included the following: (1) to determine whether megestrol acetate was associated with a decline in serum IL-6 concentrations compared to dronabinol or combination therapy; and (2) to determine whether changes in serum IL-6 after 1 month of orexigenic therapy were associated with changes in appetite, weight, and quality of life.…”

Anandamide Uptake Is Consistent with Rate-limited Diffusion and Is Regulated by the Degree of Its Hydrolysis by Fatty Acid Amide Hydrolase

“…AEA modulates the production and function of a variety of cytokines in mast and basophilic cells through the cannabinoid receptors (24). RBL-2H3 cells are of immune origin and express FAAH (25) and the CB 2 receptor (26).…”

Das endogene Cannabinoidsystem

“…Mo du la ti on ver schie de ner Zy to ki ne: IFN-γ, IL-12 und IL-2 é; IL-1 Á (è) [46] 1062 | Der Nervenarzt 9 · 2005…”

“…Sig ni fi kan te Im mun sup pres si on, ins be son de re der zel lu lä ren Im mu ni tät (An zahl und Funk ti on von B-und T-Lym pho zy ten so wie Ma kro pha gen); Ver mitt lung ver mut lich über CB2-Re zep to ren [32,55,89] Hem mung der An ti tu mor-und an ti vi ra len Wir kung von Ma kro pha gen [11,12,100] Hem mung der An ti gen prä sen ta ti on durch Ma kro pha gen [61] Hem mung der Mig ra ti on von Ma kro pha gen via CB1-und CB2-Re zep to ren [81] Hem mung der TH1-Zel len [46] Mo du la ti on ver schie de ner Zy to ki ne: IFN-γ, IL-12 und IL-2 é; IL-1 Á (è) [46] des Ze re bel lums (Ko or di na ti on von Be wegung, Ba lan ce, Hal tung), des Hip po kampus (u. a. wich tig für Ge dächt nispro zesse) und der Ba sal gan gli en (Kon trol le der Be we gung; . Ta bel le 2).…”