A T-helper-2 bias in decidua: the prostaglandin contribution of the macrophage and trophoblast

JOURNAL

Journal

ELSEVIER

of Reproductive Immunology 33 (1997) 181P187

Current

OF

REPRODUCTIVE IMMUNOLOGY

Opinion

A T-helper-2 bias in decidua: the prostaglandin contribution of the macrophage and trophoblast Rodney

W. Kelly “,*, Hilary O.D. Critchley

b

rl Medical Research Council Reproductice Biology Unit, 37 Chaltnrrs St.. Edinburgh EH3 9EW. UK b Department cd’ Obstetrics arld G.vnaecology, Unirrrsity of Edinbwgb Cmtre ,fbr Reproductive Biology, 37 Chainwrs St.. Edinburgh EH3 9E W. UK Received

Keywvrd~:

1 February

1997; received

Th2; Pregnancy:

in revised

form

19 March

1997; accepted

9 April

1997

Prostaglandins

The debate on the importance of a Th-2 shift within decidua in human 1996; Vince and Johnson, 1996) omits prostapregnancy (Guilbert, glandin-mediated immunomodulatory pathways which would have a critical influence on T cells within the utero-placental environment. The key role of the decidual macrophage has been stressed previously (Hunt, 1989; Hunt and Robertson, 1996) but there is evidence that trophoblast can also secrete cytokines and other mediators (including PGE2) that have a powerful influence on the Thl to Th2 ratio. Cytokine release from the decidual macrophage might also influence growth of T cells and NK cells, such as the phenotypically unique CD56’+ LGLs found in early decidua. Relatively few CD4 + ve cells are found in decidua (Bulmer, 1996) and there is no T-cell derived, T-cell growth factor (IL-2) in decidua (Loke and King, 1995) suggesting that T-cell growth factors such as IL-l 5, thought to be of monocyte origin (Strom et al.. 1996) might substitute for IL-2.

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Uncontrolled activation of monocytes leads to tissue damage, but the macrophage’s ability to phagocytose, present antigen and act as an accessory cell in T cell activation and replication may all have to be restricted to ensure optimum fetal growth and survival. The main suppressive mediators from the monocyte/macrophage are TGFB, IL-10 (Bogdan et al., 1992) and prostaglandin E2 (PGE2) (Kunkel et al., 1986). There is now evidence that PGE stimulates not only IL-10 production (Strassmann et al., 1994) but also, in certain cell types, TGFP (Kleinnulend et al., 1996). Therefore PGE may occupy a critical position in a cytokine cascade. This is underlined by the ability of PGE to both stimulate IL-10 and inhibit the production of IL-12 (Kraan et al., 1995). Such a switch in the ratio of IL-IO/IL-12, emphasises the modulatory role of PGE on the immune system. Suppressive actions follow from such a switch which will inhibit T cell proliferation (Taga and Tosato, 1992) and, NK cell reactivity (Chehimi et al., 1992) effect class switching in B cells (Phipps et al., 1991; Morris et al., 1994) and induce a Th-2 bias in CD4+ T cells (Kaplan et al., 1996; Trinchieri and Gerosa, 1996) (Table 1). PGE may however be controlling more fundamental events in decidua since either directly (Mannie et al., 1995) or through its effect on IL-10 (Suzuki et al., 1995; Groux et al., 1996) it can induce antigen-specific T cell anergy. Table 1 PGE effects

Direct

on T cells and NK cells Effect

Reference

Inhibits IL-2 release Elevates CAMP and inactivates Th-1 cells PGE inactivates cytotoxic activity

(Chouaib et al., 1985) (Betz and Fox, 1991)

efftcts

T cells

NK cells

In a murine model PGE changes phenotype of a subset of peripheral NK cells to that of characteristic metrial gland, non-cytotoxic. LGL Indirect

T cells

NK cells

@cts

through

(Goto et al., 1983: Scodras al., 1990) (Linnemeyer and Pollack, 1993)

A PC

Induction of antigen-specific anergy Stimulation of IL- IO/IL- 12 ratio induces Th-2 switch and decreases T cell proliferation Reduced IL-12 from above leads to reduced activation Reduced IFN-18 from T cell switch

(Groux (Kraan

et al.. 1996) et al., 1995)

(Chehimi (Wegmann

et al.. 1992) et al.. 1993)

et

The role of prostaglandins in both murine and human decidua has been discussed extensively (Clark, 1985, 1991; Mathews and Searle, 1987; Parhar et al., 1989) and a suppressive role was postulated. However, their relevance as suppressive agents was questioned (Clark, 1991) on the basis of a continuing pregnancy in women taking aspirin or indomethacin and on experiments in which mice were administered indomethacin. We now know that there are two forms of cyclooxygenase (the enzyme responsible for prostaglandin synthesis) one constitutive (COX-1) and one inducible (COX2). The inducible form is thought to be the major form in monocytes (Endo et al., 1996). This localised production of prostaglandin might not be fully suppressed by indomethacin or aspirin as found in several in vivo studies with non-steroidal anti-inflammatory drugs (Horton et al., 1973; Knuth et al., 1989). What is clear is that the production of PGE by macrophages in (Tawfik et al., 1986; general (Humes et al., 1977), decidua in particular Hunt, 1989; Parhar et al., 1989) and trophoblastic villi (Kelly et al., 1995) could exert a powerful influence on T cells. Extravillous trophoblast can synthesise IL-10 (Roth et al., 1996) which would complement the PGE effect and might also be PGE-dependent. A participation of the trophoblast in suppressive mechanisms introduces a further complication since GM-CSF which might have a trophic action on the trophoblast (Heyborne and Silver. 1996), is in turn down-regulated by message destabilisation induced by IL-10 (Brown et al., 1996) whose own mRNA is subjected to delayed inhibition. As inflammatory mediators, prostaglandins are synthesised in response to trauma and in vitro many tissue and cell preparations produce PGE which can pre-empt experimental manipulation. This problem has been avoided in recent experiments on cytokine synthesis in whole blood that has been treated without manipulation (Kraan et al., 1995) but reflects the dynamic response of prostaglandin synthesis which is mediated through COX-2, an immediate early gene (Maier et al., 1990). Prostaglandins can also be pro-inflammatory by mechanisms exerted in perivascular cells (Kelly, 1994) where levels in decidua are kept low by progesterone dependent prostaglandin dehydrogenase (Cheng et al., 1993). The effect of progesterone may however be different in decidual and placental macrophages. These cells are subjected to very high levels of progesterone from the trophoblast and this may be responsible for the phenotype change favouring PGE production (Hunt and Robertson, 1996). A reasonable hypothesis is that equilibrium within decidua involves a significant basal release of IL-IO. But at the time of implantation and trophoblast invasion (Kennedy, 1988) or in the presence of infection (mimicked by LPS) monocyte/macrophage activation is tolerated to a limited extent but the down-regulation, mediated by PGE and IL-10 from the

monocyte and trophoblast is accentuated producing the biasing effect (Guilbert, 1996). The effects of this PGE/cytokine release on T cells will be 3-fold. First, there will be effects on T cell proliferation through either a direct inhibition of IL-2 (Rappaport and Dodge, 1982; Barrera et al., 1996) or indirectly through a stimulation of IL-10 (Taga and Tosato, 1992) accounting for the absence of IL-2, highlighted as a critical feature of decidua (Guilbert, 1996; Vince and Johnson, 1996). Second, the Thl/Th2 balance will be skewed in favour of Th2 responses, both by PGE raising intracellular CAMP levels within CD4 + ve cells, with a differential effect on Thl and Th2 cells (Betz and Fox, 1991) and through the induced IL-10 production. Third, anergy could be induced in T cells, which might be for specific trophoblast antigens. This could either be due to antigen presentation in the presence of IL-10 (Groux et al.. 1996) or due to PGE (Mannie et al., 1995). In keeping with a dynamic system of regulatory feedback loops, the production of PGE will be self-limiting since IL- 10 destabilises messages which contain the AU instability element in their 3’ untranslated region (Brown et al., 1996). COX-2 has such a sequence in its message (O’Banion et al., 1992) and is known to be inhibited by IL-10 (Mertz et al., 1994). Potential stimulatory cytokines such as GMCSF will be down-regulated (Brown et al., 1996) whilst auto-inhibition by IL-10 which is significantly delayed will eventually restore the status quo. In summary, several negative feedback mechanisms involving a primary drive from the trophoblast as well as tissue macrophages, would operate to maintain an homeostasis in decidua, in which the interests of the growing fetus are balanced with those of the mother. In this equation the prime interaction may be between the trophoblast and monocyte/macrophage but the release of PGE and IL-10 ensures that any cell-mediated inflammatory response in receptive maternal tissue is muted.

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