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Department of Medicine College of Medicine, University of Arizona Tucson, Arizona 85724-5099
Address all correspondence and requests for reprints to: Seymour Reichlin, Department of Medicine, College of Medicine University of Arizona, P.O. Box 245099, Tucson, Arizona 85724-5099. E-mail: reichlin{at}u.arizona.edu
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But this relatively tidy scheme has gone seriously awry in the field of cytokines, which comprise a huge number of cell-derived stimulating and inhibitory factors. Although these pleiotropic factors exert important effects on metabolic, endocrine, and neural activity, most were initially recognized as factors involved in innate or acquired immunity, or as regulators of hematopoiesis, and their cardinal names often indelibly bias the way we think about their functions. "Endogenous pyrogen" (the circulating fever-causing factor induced by bacterial toxin) has mercifully been renamed interleukin-1. Interleukin-2 was first recognized as a T lymphocyte growth factor, and IL-6 was initially called B-cell differentiating factor. Tumor necrosis factor and cachectin were isolated and named on the basis of different bioassays, one that measured tumor regression after injections of bacterial toxin, and the other based on wasting and impaired fat deposition. Later they were shown to be identical molecules.
And this brings us to leukemia inhibitory factor (LIF), first described a little more than a decade ago. LIF was initially identified as a product of mouse macrophages that brought about the differentiation (toward maturity) of a mouse monocytic leukemia cell line (1). The human homologue (mol wt approximately 20,000) was identified by screening a genomic library with a murine complementary DNA probe (2); the human peptide has 78% sequence identity with the mouse factor. Within 3 yr of its discovery, LIF had been shown to be identical with the cholinergic differentiation factor of myocardial cells (3), with a lipoprotein lipase inhibitory factor secreted by melanoma cells (4), and to have many cytokine-like activities including that of osteoclast stimulation (5). These properties overlap with those of several other cytokines, all of which exert their tissue effects by binding to specific class 1 cytokine receptors to form dimers of a common transducer termed gp130 (6).
LIF first emerged as a pituitary secretion during studies of vascular growth regulating factors. In addition to vascular endothelial growth factor (VEGF), follicular cells of the pituitary (which secrete none of the classical pituitary hormones) were shown to secrete a factor that inhibited endothelial growth in cells derived from bovine aorta. Ferrara et al. (7), who first made this observation in 1992, proposed that LIF played a role in regulating the peculiar vascularity of the pituitary.
From this point on, Melmed and his colleagues have carried out a number of studies in an attempt to identify a larger function of LIF in pituitary regulation. In earlier work (cited in Refs. 8 and 9), they showed that LIF is expressed in human and mouse anterior pituitary, that its expression is stimulated by bacterial endotoxin, that LIF is expressed by corticotroph cells as well as by folliculostellate cells, both in the pituitary and in the mouse corticotrope cell line, AtT-20, and that LIF injection induces acute release of ACTH in mice and in monkeys.
Now, in the two papers published in this issue of
Endocrinology (8, 9), the Melmed group has probed further to
determine whether LIF is an essential mediator of the pituitary-adrenal
response to emotional and inflammatory stress. They confirmed that the
AtT-20 cell line secretes LIF and that LIF messenger RNA (mRNA)
expression was greatly stimulated by IL-1ß and by tumor necrosis
factor-
to a lesser extent. They found that the two cytokines were
synergistic as is the case for a number of other biological systems.
They also showed that both LIF and IL-1ß stimulated ACTH secretion
in vitro, and in intact mice, and that IL-1ß enhanced LIF
mRNA expression in both the hypothalamus and in the pituitary.
In a crucial experiment, they determined whether mice with selective knockout of LIF released ACTH and corticosterone following the injection of IL-1ß ip. Their answer to this question has some ambiguities that prevent an absolute conclusion. Baseline corticosterone obtained under anesthesia in LIF knockout mice was the same as that of wild strain animals, but baseline ACTH levels were significantly less. After injection of IL-1ß ACTH and corticosterone blood levels rose in both knockout and the wild strains, but the zenith of the responses were significantly less in the LIF knockout animals. The conclusion to be drawn is not obvious. Although the magnitude of the ACTH response is less in the knockout mice, the proportional increase of ACTH is virtually identical in the two strains. One could argue, therefore, that the mass of ACTH secreting cells (or the complex cell machinery for synthesis and release of ACTH) was less in the LIF-deficient animals. In keeping with the known growth stimulating and differentiating properties of LIF, it could then be argued that LIF acted, not as an acute mediator of IL-1 effects on the pituitary-adrenal axis, but rather as a trophic or cell growth factor.
To further clarify this issue, these workers went on to show that pituitary concentration of POMC mRNA was markedly reduced in unstressed LIF-deficient mice, and that, in contrast to the wild-type, restraint stress did not stimulate its expression. Baseline hypothalamic CRH was at least normal, or elevated in the LIF knockout animals. The crucial finding in this series of experiments was that the injection of LIF increased the expression of POMC in the LIF-deficient animals. One could argue from their two studies that LIF plays an important role in activating the hypothalamic-pituitary-adrenal axis during stress and inflammation. An equally appealing interpretation is that the synthesis and secretion of POMC-ACTH is dependent on LIF secreted by the pituitary as a paracrine and/or autocrine factor and that the amount of POMC (or its cellular synthetic machinery), upon which other regulatory factors converge is partly determined by the intrinsic secretion of LIF. In keeping with this interpretation is the finding (also by the Melmed group), that transgenic mice hyperexpressing the LIF gene show abnormal pituitary morphology including Rathke’s cleft cysts, and increased numbers of ACTH immunopositive cells (10).
This elegant series of papers on pituitary LIF and its function should be put in context with what is known of the effects of Il-1 on ACTH regulation. Although it had been recognized for many years that endotoxin and inflammatory illness stimulated the pituitary-adrenal axis, it was not until the study by Besedovsky et al. (11) showing that recombinant human IL-1ß stimulated ACTH and corticosterone release in the rat that the role of cytokines in ACTH release could be studied definitively. The bulk of work since then has confirmed that, although Il-1ß under certain circumstances can stimulate ACTH release from the anterior pituitary, the major site of action is at the level of hypothalamic CRH secretion (12). Findings that support this conclusion are that CRH levels in hypophysial-portal blood are increased by systemic IL-1 injection (13), that CRH mRNA expression in the hypothalamus is increased by IL-1 (14), that administration of anti-CRH antibody inhibits IL-1-induced ACTH release (15), and that IL-1 releases CRH from perfused hypothalamic cells (16). In several studies (but not all), direct addition of IL-1ß to pituitary cells has had little or no immediate effect on ACTH secretion (12, 16, 17). Although the acute ACTH response to IL-1 thus appears to be mainly by way of hypothalamic release of CRH, its ACTH stimulating activity in long-term incubations and in corticotropin-secreting tumors suggests that it also has a trophic effect on adrenotropic cells. In that respect, IL-1, though it acts through a different class of cytokine receptors, shares some of the properties that have been demonstrated for LIF.
Received March 6, 1998.
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