Leukaemia Inhibiting Factor and Endocannabinoids

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Human reproductive fluids, such as seminal plasma, mid-cycle oviductal fluid, follicular fluid, amniotic fluid, as well as human amniotic fluid and human milk have been reported to contain AEA, N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA) in the low nanomolar range, i.e. from 3 nM of AEA in the follicular fluid to 67 nM of OEA in human milk (Schuel et al. 2002b). This suggests that endocannabinoids might regulate multiple physiological and pathological reproductive functions in humans, implying that exogenous cannabinoids delivered by marijuana smoke could impact these processes. Consistent with the hypothesis that endocannabinoids adversely affect human fertility, we have recently found a fall in FAAH activity and expression in the T lymphocytes of women experiencing miscarriage (Maccarrone et al. 2000) and a rise ( 4-fold) in blood AEA levels of the same subjects, compared to women with normal gestation (Maccarrone et al. 2002). The other components of the endocannabinoid system, like the AEA membrane transporter (AMT) and CBi receptors, were not affected (Table 3).

Table 3. FAAH activity, AMT activity and CBi receptor binding in women who miscarried and those who did not (data from Maccarrone et al. 2001)

Parameter

Pregnant women

Miscarrying women

FAAH activity3

133 ± 9(100%)

48 ± 5 ( 36%)*

AMT activityb

50 ± 4(100%)

49 ± 4(100%)

CB1 bindingc

20,380 ±1,930 (100%)

20,400 ±1,795 (100%)

AMT, anandamide membrane transporter; FAAH, fatty acid amide hydrolase.

aExpressed as pmol.min-1.mg protein-1.

bExpressed as pmol.min-1 .mg protein-1.

cExpressed as cpm.mg protein-1.

*p<0.0001 vs pregnant women (p>0.05 in all other cases).

AMT, anandamide membrane transporter; FAAH, fatty acid amide hydrolase.

aExpressed as pmol.min-1.mg protein-1.

bExpressed as pmol.min-1 .mg protein-1.

cExpressed as cpm.mg protein-1.

*p<0.0001 vs pregnant women (p>0.05 in all other cases).

Peripheral T lymphocytes regulate fertility at the feto-maternal interface, by producing type 1 T helper (Thi) and type 2 T helper (Th2) cytokines (Piccinni et al. 1998). Th2 cytokines, such as interleukin (IL)-3, IL-4 and IL-10, favour blastocyst implantation and successful pregnancy by promoting trophoblast growth either directly or indirectly through the inhibition of natural killer (NK) cell activity and the stimulation of natural suppressor cells. Conversely, Th1 cytokines, such as IL-2, IL-12 and interferon-y (INF-y), impair gestation by causing direct damage to the trophoblast, by stimulating NK cells and by enhancing tumour necrosis factor-a (TNF-a) secretion by macrophages. Also, trophoblasts stimulate release of pro-fertility Th2 cytokines from T lymphocytes (so-called "Th2 bias"), while suppressing the anti-fertility Th1 bias. Progesterone (P) favours the Th2 bias, thus stimulating the release from T lymphocytes of LIF, which in turn favours fetal implantation and survival (Szekenes-Bartho and Wegmann 1996; Stewart and Cullinan 1997; Duval et al. 2000).

P also stimulates FAAH activity and expression in human T lymphocytes (Maccarrone et al. 2001) by enhancing the promoter activity of the FAAH gene (Maccarrone et al. 2003c). Regulation of FAAH expression was observed also upon lymphocyte treatment with Th1/Th2 cytokines: IL-4 and IL-10 enhanced FAAH, while IL-2 and INF-y reduced it (Maccarrone et al. 2001). Unlike FAAH, the other proteins of the endocannabinoid system were not affected by P or by any of the cytokines tested (Maccarrone et al. 2001), pointing to FAAH as the "check point" for AEA degradation during pregnancy.

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