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The Unsolved Enigmas of Leukemia Inhibitory Factor

Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Key Words. Leukemia inhibitory factor • Embryonic stem cells • Polyfunctionality

Donald Metcalf, A.C., M.D., Professor Emeritus, Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville Victoria 3050, Australia. Telephone: 61-3-9345-2555; Fax: 61-3-9347-0852; e-mail: metcalf{at}wehi.edu.au

	ABSTRACT

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
Leukemia inhibitory factor (LIF) is a polyfunctional glycoprotein cytokine whose inducible production can occur in many, perhaps all, tissues. LIF acts on responding cells by binding to a heterodimeric membrane receptor composed of a low-affinity LIF-specific receptor and the gp130 receptor chain also used as the receptor for interleukin-6, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. LIF is essential for blastocyst implantation and the normal development of hippocampal and olfactory receptor neurons. LIF is used extensively in experimental biology because of its key ability to induce embryonic stem cells to retain their totipotentiality. LIF has a wide array of actions, including acting as a stimulus for platelet formation, proliferation of some hematopoietic cells, bone formation, adipocyte lipid transport, adrenocorticotropic hormone production, neuronal survival and formation, muscle satellite cell proliferation, and acute phase production by hepatocytes. Unwanted actions of LIF can be minimized by circulating soluble LIF receptors and by intracellular suppression by suppressors of cytokine-signaling family members. However, the outstanding problems remain of how the induction of LIF is mediated in response to demands from such a heterogeneity of target tissues and why it makes design sense to use LIF in the regulation of such a diverse and unrelated series of biological processes.

	INTRODUCTION

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
It is now almost 15 years since the purification and cloning of leukemia inhibitory factor (LIF), and recognition began of the disturbing, but remarkable, pleiotropic actions of LIF. Despite the reluctance of pharmaceutical companies to become involved with an agent with pleiotropic, and thus potentially "adverse," actions LIF has been shown to be relatively nontoxic [1] and has completed one phase II clinical trial. It has therefore proceeded well enough down the difficult pathway from discovery to clinical exploitation.

Of the many observed actions of LIF, its outstanding ability to preserve the totipotentiality of murine embryonic stem cells has assured it a continuing role in experimental biology [2, 3]. Despite this, LIF seems now to have entered that peculiar limbo world occupied by many "middle-aged" regulators in which the regulator remains familiar but is no longer fashionable. LIF continues to be studied actively by disparate groups of biologists, but the key word is disparate. The hematologists, neurobiologists, muscle cell biologists, bone biologists, endocrinologists, and reproductive biologists involved are each steadily expanding knowledge of their particular facet. What appear to be missing are serious attempts to link these disparate pieces of biology into a coordinated framework that provides a cogent rationale for the existence of LIF. Why does the body use a pleiotropic molecule like LIF? This would appear to be a recipe for disaster, yet there must be a compelling reason. So far, no one appears willing or able to address the central questions being posed by LIF or the allied pleiotropic molecules interleukin (IL)-6, IL-11, and oncostatin M (OSM).

In the hope of refocusing attention on some of the major biological problems posed by LIF, this review briefly summarizes, some of the recent work in the various fields in which LIF action is being explored. The referencing is idiosyncratic, and for this I apologize. It often merely singles out a few recent publications in each subfield as illustrative examples. This cavalier approach will at times be unfair to those originally describing key phenomena, but the referencing is mainly designed to signal that a subfield is substantive and needs serious consideration when trying to synthesize general ideas regarding LIF.

	LIF AS A CANDIDATE HEMATOPOIETIC REGULATOR

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
Murine LIF is a glycoprotein with a 180-amino-acid single 4--helix polypeptide chain. LIF was purified from medium conditioned by Krebs-II ascites tumor cells and then cloned from a murine T-lymphocyte cDNA library as a factor able to induce macrophage maturation and terminate self-renewal of the undifferentiated and highly clonogenic murine myeloid leukemia, M1 [4, 5]. Combination of these actions suppressed the leukemic population, hence the name assigned. Cloning of the corresponding human LIF cDNA was performed using the murine cDNA as a probe [6]. The name "leukemia inhibitory factor" has proven to be quite inappropriate for this highly polyfunctional molecule, but at least it has preserved LIF from the indignity of ending up merely with an anonymous IL- or CD-barcode number.

LIF was presumed to be a factor playing some regulatory role in hematopoiesis and possibly having a special suppressive action on some myeloid leukemias. It is odd that there appears to have been no subsequent extensive attempt to explore the possible suppressive action of LIF on primary human myeloid leukemic cells in vitro, although this would be easy enough to explore in clonal cultures.

In initial studies, LIF appeared to have no obvious ability to stimulate hematopoietic colony formation in vitro [7], although it potentiated mouse megakaryocyte colony formation stimulated in vitro by IL-3 [8]. In subsequent studies, LIF has been shown to reproducibly enhance blast colony formation by murine marrow cells when stimulated by Flk ligand, a system in which the blast colony cells can be shown to be macrophage progenitor cells, many with an ability to form dendritic cell progeny [9]. Further, LIF was able to stimulate the proliferation of the human factor-dependent hematopoietic cell line, DA [10], and the factor-dependent murine leukemic cell line, GB2, with the formation by the latter cells of undifferentiated blast colonies, although GB2 cells readily differentiate when stimulated by other growth factors [11]. Possible actions of LIF in enhancing stem cell proliferation have been reported [12–14], but LIF has not clearly emerged as being of high importance for the in vitro culture of hematopoietic stem cells.

When injected into mice, LIF elevated megakaryocyte and platelet numbers, with peak responses occurring 7-10 days after commencement of injections [15]. Other LIF-induced changes were an increase in erythrocyte sedimentation rate and elevated calcium to albumin ratios in the serum. In primate studies, LIF exhibited equivalent potency in elevating platelet levels to those shown by IL-6 or IL-11 [16]. The subsequent approval of IL-11 for clinical use as a platelet-stimulating agent owes more to a highly focused development program and astute clinical trials than to any major difference among these three agents in their ability to promote platelet formation.

It is now well accepted that hematopoietic regulators are polyfunctional and do not merely stimulate cell proliferation. LIF receptors on murine hematopoietic populations are mainly restricted to cells of the monocyte lineage [17], but no attempts have been made to establish whether LIF has actions on maturation induction or functional activation of monocytic cells, although functional activation of platelets by LIF has been described [18].

	LIF AND EMBRYONIC STEM CELLS

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
Early in the experimental work on LIF, astute lateral thinking raised the possibility that LIF might be the active agent produced by underlayer cells that was needed to sustain the totipotentiality of cultured murine embryonic stem (ES) cells. This proved to be the case [2, 3], and this finding had a major impact on work with ES cells. Use of LIF to maintain the pluripotentiality of murine ES cells has become standard, and, coupled with gene manipulation by homologous recombination, has permitted the generation of the various knockout and knockin mutant mice that are now central to current advances in biology and pathology. LIF may not be unique in this role but is the most active and most often used agent. Curiously, maintenance of totipotentiality in human ES cell lines does not exhibit a clear dependency on LIF [19].

It is intriguing why LIF has a differentiation-inducing action on leukemic cells but a differentiation-preventing action on normal ES cells. Logic suggests that a common molecular pathway is likely to be involved for much of both responses, but how does the end result become opposite in the two types of responding cells? Molecular mechanisms are beginning to be identified that appear necessary for maintenance of self-renewal in response to LIF signaling, and, to date, Stat3 and Oct-3/4 seem to play key roles [20].

There is current vigorous debate on the nature of the stem cells being detected in adult tissues. How multipotential are these cells from adult organs? Are some the equivalent of ES cells? It is remarkable with all this current activity that no one seems to have established clearly what happens to the ES-type cells of the blastocyst as the embryo develops. Do they vanish because all become committed, or do some persist in various organs? Initial cell numbers in the blastocyst are small, but can some of these cells engage in amplifying self-generation? The defining properties of a stem cell that would identify it as of embryonic type presumably would include a certified ability for sustained self-generation plus retention of totipotentiality, the latter a cumbersome property to establish by blastocyst injection and analysis of resulting chimeras. Nevertheless, it should be technically possible to obtain some answers, particularly from cultures of cells from early embryos, with or without LIF. It is curious that the use of LIF seems not to have been prominent in current efforts to culture totipotential cells from adult organs. Why not? If the key totipotentiality-preserving action of LIF on ES and blastocyst cells persists for any surviving cells of these types in later life, there should be a marked difference between cultures with or without LIF. On this question, why are LIF^-/- mice not being used in any of the current adult stem cell experiments? Indeed, do LIF^-/- mice even possess cells in the marrow or elsewhere that are able to populate other organs?

	CONSEQUENCES OF EXCESS LEVELS OF LIF

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
Studies were undertaken early to examine the possible pathological consequences in mice of sustained excess LIF levels. The original system used was to inject syngeneic normal recipients with factor-dependent FDC-P1 cells that had been engineered to constitutively overproduce LIF [21]. The injected FDC-P1 cells seeded primarily in the marrow and spleen and built up stable populations of LIF-producing cells in these sites. The engrafted animals lost weight and after 2 or 3 months developed a terminal cachectic-like appearance coupled with a curious, excited, hypermotile state (Fig. 1A). At autopsy, there was extensive overgrowth of medullary bone tissue in the ends of the long bones (Fig. 1B); variable calcification in the liver, heart, and skeletal muscle; loss of all fatty tissue; thymus atrophy; a small friable pancreas; and an absence of corpora lutea in the ovaries [21, 22]. What was not reported in this original description, because initially only female mice had been engrafted, was that in grafted males, the seminiferous tubules of the testes became entirely depleted of spermatogonia (Fig. 1C).

View larger version (75K): [in this window] [in a new window]   Figure 1. Excess levels of LIF cause a fatal disease. Features of LIF-excess mouse include: A) General appearance of a mouse (lower) with excess levels of LIF. The mouse shows profound loss of adipose tissue, is hypermotile but near death. B) Overgrowth of bone tissue and osteoblasts in the medulla of long bones. C) Complete loss of spermatocytes from the seminiferous tubules of the testis.

	LIF KNOCKOUTS AND BLASTOCYST IMPLANTATION

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
Most would now take the view that inactivation of a gene provides "bottom line" data on the functions of the gene product, or at least those functions that are not replaceable by other gene products. However, the use of mice for this purpose has major limitations unless obvious pathology develops, or cell populations can be identified as behaving in an abnormal manner. Inevitably, initial data on the consequences of gene deletion are incomplete. LIF^–/– mice could be produced in expected Mendelian ratios and appeared to develop into healthy young adults, an astonishing outcome given the multiple functions of LIF. One dramatic abnormality, however, was that LIF^–/– females were absolutely unable to become pregnant [12, 24]. The likely basis for this deficiency is the crucial absence of estrogen-induced LIF synthesis in the uterine wall at the time of blastocyst implantation [25–27]. A LIF^–/– blastocyst will form a normal-enough embryo if implanted in a LIF⁺/⁺ uterus, and pregnancies can be achieved in LIF^–/– mice by injection of LIF [27]. Although a number of agents and hormones are of known importance for implantation, LIF is irreplaceable. It seems likely that in a subset of infertile women in which in vitro fertilization implantation fails, LIF production in the uterine wall is subnormal [28], and the clinical use of LIF in such subjects is under trial.

While LIF^–/– mice appear to behave normally enough, they have been reported to have major anatomical abnormalities of the hippocampus [29] and an accumulation of excess numbers of olfactory receptor neurons [30]. Appropriate stress stimuli might reveal other functional deficiencies in LIF^-/- mice.

	LIF PRODUCTION SITES

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
LIF mRNA is transcribed in multiple organs [31], but there is less information on which organs are major producers of LIF protein and, in particular, the range of different cell types that can be involved. Like most cytokines, LIF production is highly inducible with a wide range of inducing agents according to the cell type involved. In uterine tissue, LIF production by uterine gland cells changes abruptly prior to implantation [26, 32]. LIF production has also been reported in the blastocyst [33], thymus and lung [34], hypophysis [35], cardiac muscle [36], kidney [37], neuronal tissue following injury [38], and in the skin [39].

	THE PROMISCUOUS LIF RECEPTOR

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
A specific membrane receptor for murine LIF (gp190) (termed by some LIFRß) was cloned and shown to be a member of the cytokine receptor family with a typical juxtamembrane WSXWS motif and spaced cysteine residues in the extracellular domain [40]. The partner receptor chain for the LIF receptor is gp130, which also partners the specific receptor chain for IL-6 (Fig. 2) [41]. This sharing of receptor subunits provides one reason why some of the pleiotropic effects of LIF are also exhibited by IL-6. The two factors do of course differ in some actions, the differences being based in part on differing tissue patterns of expression of the specific low-affinity receptor chains. Unexpected data documented that OSM can use the LIF/gp130 receptor [42] although it has its own specific receptor [43]; that cardiotrophin-1 also uses the LIF/gp130 receptor, probably if in association with a third specific protein [44]; and that ciliary neurotrophic factor (CNTF) can use the LIF/gp130 receptor if it binds first to a specific CNTF- chain (Fig. 2) [45]. This receptor sharing may be partly the reason why deletion of the gp130 gene is embryolethal [46], whereas deletion of the LIF gene is not.

View larger version (26K): [in this window] [in a new window]   Figure 2. Subunit sharing in the receptors for the LIF/IL-6 family of cytokines. LIF-specific receptor chains (yellow) are present in the receptor complexes for LIF, OSM, CNTF, and cardiotrophin-1 (CT). The gp130 receptor subunit (blue) is also present in these receptor complexes plus those for IL-6 and IL-11. Additional ligand-specific chains are present in the receptors for CNTF, CT, IL-6, IL-11, and an alternate OSM receptor.

The problem posed by the multiorgan sites of LIF production has been rendered less acute, at least in the mouse, by the documentation of sufficiently high levels of circulating soluble LIF receptors to block the action of any LIF in the circulation [51]. This mechanism could restrict LIF action to a particular local site of active LIF production. Thus, in pregnancy, local uterine LIF production rises, but circulating receptor levels rise even higher [52], presumably protecting the body from generalized LIF actions. Soluble LIF receptors have also been described in human serum, and during human pregnancy, soluble LIF receptor levels rise as in the mouse [53, 54].

For 20 years hematologists have had to face the puzzling fact that a single regulator, acting through a single receptor type, can elicit multiple responses in the responding cells—not simply proliferation but also survival, differentiation commitment, maturation initiation, and functional stimulation of the mature cells. The documentation of differing functional domains in the receptor chains that allow initiation of distinct signaling events has gone some way to explain how multiple responses can be initiated by activation of a single receptor type.

For highly pleiotropic agents, such as LIF or IL-6, the problem is not much worse. The differences in elicited cell behavior seem dramatic, for example, bone formation versus neuronal signaling, but these differences simply reflect the widely differing normal functions of the responding cells. These functions may well be activated by broadly comparable molecules with those operating in hematopoietic cells [55], but there is virtually no information on possibly differing signaling components or novel combinations of nuclear transcription factors, in particular cell types expressing LIF receptors, that might permit novel responses to LIF.

If LIF can be regarded as eliciting a set of positive cellular responses, then model builders insist that, for stability of such populations, a balancing set of negative regulators must exist. It is not sufficient to have a transient induction system for LIF and possibly not enough to have soluble LIF receptors able to block LIF action.

It is of interest that for LIF, IL-6, and OSM, there is now an additional well-defined set of intracellular agents able to block, reduce, or terminate ligand-elicited signaling. These agents are the eight SH2-containing members of the suppressors of cytokine signaling (SOCS) family of proteins: cytokine-inducible SH2-containing protein (CIS) and SOCS 1-7 [56]. Typically, production of these SOCS proteins is rapidly induced by LIF or IL-6 signaling, resulting in the transient production of SOCS protein. Complete inhibition of LIF signaling has been documented in M1 cells that are overexpressing SOCS-1, -3, and probably -5 [57]. The half-lives of SOCS proteins are short. They bind to elongins B and C [58] and likely are then targeted for endosomal degradation along with any other protein bound to the SOCS protein. The SOCS proteins represent highly potent modulators of LIF signaling, but information is sparse on which LIF-responsive cell types produce which SOCS proteins. In the case of LIF action in eliciting adrenocorticotropic hormone (ACTH) production by the pituitary, SOCS-3 appears to be the dominant suppressor of the response [59].

	THE PLEIOTROPIC ACTIONS OF LIF

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
Soon after the sequencing of LIF, a number of investigators recognized that molecules they had been working with were in fact LIF. Thus, a cachexia-inducing agent blocking lipid transport to adipocytes was identified as LIF [60]. Hepatocyte-stimulating factor III, able to induce liver cells to produce acute-phase proteins, was identified as LIF [61]. LIF was also recognized to be the factor capable of switching autonomic nerve signaling from adrenergic to cholinergic mode [62].

There have followed a range of reports of LIF actions, often in vitro, where LIF is not claimed necessarily as the only agent capable of eliciting the response and often is acting in collaboration with another agent. The list includes the following actions.

Kidney Actions
In collaboration with transforming growth factor ß2, LIF produced by the ureteric buds induces clumps of cultured mesenchymal cells to differentiate into glomeruli and tubules [63–65].

Neuronal Functions
There have been multiple reports of LIF action on neuronal tissue, which extend the original findings in LIF^–/– mice: A) LIF enhances the survival of sensory and motor neurons [66]; B) LIF stimulates the formation of sensory neurons from cultures of neural crest cells [66]; C) LIF, with fibroblast growth factor (FGF) and epidermal growth factor, can allow the protracted in vitro proliferation of multipotential human neural progenitor cells [67]; D) LIF prevents oligodendrocyte death in animal models of multiple sclerosis [68]; E) Excess LIF levels reduce the number of calbindin-positive Purkinje cells in the cerebellum [69]; F) LIF enhances migration of inflammatory macrophages to damaged neuronal tissue [70], and G) LIF inhibits the maturation of olfactory receptor neurons in vivo, and excess cell numbers are found in LIF^–/– mice [30].

Endocrine Actions
LIF has been reported to have multiple effects on endocrine organs or their target tissues: A) LIF suppresses the proliferation in vitro of normal human breast epithelial cells and breast cancer cells [71]; B) LIF is a major regulator of ACTH production in the pituitary, and its actions are blocked by SOCS-3 [59]; C) Conversely, LIF inhibits the production of prolactin and growth hormone [72]; D) LIF promotes the production of primary follicles in the ovary from primordial follicles [73], and E) LIF reduces testosterone synthesis by Leydig cells [74] but, puzzlingly, also enhances the proliferation of primordial germ cells and spermatocyte differentiation [75, 76].

Bone Actions
In vitro studies have extended the original observation of excess bone formation in mice with excess LIF levels: A) LIF increases calcium resorption from bone and increases osteoclast numbers [77] and B) conversely, LIF enhances bone formation by binding directly to osteoblasts and increasing osteoblast numbers [78]. However, culture conditions were observed to influence whether LIF inhibited or stimulated bone formation [79].

Muscle Actions
LIF can stimulate the proliferation of muscle satellite cells [80] and can ameliorate muscle fiber degeneration in vivo in mdx mice lacking dystrophin [81]. LIF is a hypertrophic agent for cardiac muscle [82] and also for cultured cardiac myocytes [83] and reduces apoptosis in such cells [84].

Miscellaneous Effects
LIF has been reported to stimulate the proliferation of neonatal mouse epidermal melanocytes [85] and keratinocytes from patients with amyotrophic lateral sclerosis [86] and to enhance mast cell proliferation [87]. When combined with basic FGF, LIF was noted to enhance the formation of capillary-like structures in cultures of an embryonic endothelial cell line [88]. Finally, LIF has been reported as possibly being involved in reducing vertical transmission of HIV-1 virus through the placenta [89].

This list is almost certainly incomplete but serves to document the extraordinary range of biological events in which LIF has been observed to have an action.

	IMPLICATIONS OF THE PLEIOTROPIC NATURE OF LIF

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 
At first sight, the bizarre range of reported tissue responses to LIF is the most puzzling aspect of LIF action. This is because there is no situation in developmental biology or in disease where the function of such a disparate collection of tissues needs to be coordinated or simultaneously regulated.

Responsiveness of a population to LIF action depends on expression of the LIF receptor complex, with expression of the low-affinity LIF receptor presumably usually being the limiting factor because expression of gp130 is much more widespread. Virtually nothing is known of the inductive signals leading to receptor synthesis or expression. What molecular mechanisms initiate the transcription of LIF receptor mRNA and what dictates whether transmembrane or soluble receptors will be produced and in what relative amounts?

The spectacular pleiotropic actions of LIF are likely to be based mainly on the unusually broad range of cells expressing the receptor, with quite possibly an unremarkable set of signaling events [48] then eliciting cellular responses that are very different simply because the responding cells are programmed to exhibit radically different functions.

Glimpses of how one regulator might be able to achieve disparate responses do not explain why the use of LIF for a multiplicity of functions might have an advantage over a more logical system in which a set of more selective regulators could be used. LIF is a typical 4--helix glycoprotein, similar to other hematopoietic regulators, and there is nothing obvious about its structure that might confer superior properties on the molecule.

However, it is even more puzzling to consider why the body has chosen to use differing cell types to produce LIF and, most puzzling of all, why a wide variety of inducing signals operates to induce transcription of this single gene. Is there a common signaling pathway for LIF gene activation? How can this be activated by such differing signals, and how is the cellular production of LIF coordinated and regulated in different local sites? It is commonly assumed that end cell numbers control levels of cytokine production, but this is incorrect, even for proliferative cytokines [90]. Where a factor has no uniform action in altering target cell numbers, this method of feedback control is even less likely. The more likely mechanism for controlling such cytokine production is a demand-generated one in which completion of a needed response removes the initiating signal for elevated cytokine production. The true diversity of the biology of LIF lies therefore in the diverse biology of the inducing systems. Whether the needed responses are, for example, extra bone formation, extra platelets, improved neuronal survival, or blastocyst implantation, each of these situations must somehow be able to generate a signal regulating LIF production. How can such a bizarre assortment of inducing signals function in a rational manner?

We are at present faced with two sets of data about LIF that are not in agreement. On the one hand, from in vitro studies and some in vivo data, LIF is able to induce an amazing variety of measurable responses. On the other hand, LIF^–/– mice seem remarkably normal apart from an inability to become pregnant. So, is LIF a master molecule or a versatile bit player whose various roles can easily be taken over by one or another of a variety of molecules?

Resolution of this paradox depends heavily on the adequacy of knockout mice, and there are profound limitations to mice, particularly where neuronal properties are being investigated. Furthermore, knockout mice live in a near stress-free environment. How might they perform out on the street?

The truth about LIF may well be somewhere in the middle. There are other LIF-like molecules (IL-6, IL-11, and OSM), and these can elicit many responses that are similar to those of LIF. In addition, for particular end organs, there clearly are other agents able to achieve similar end results by quite independent mechanisms, e.g., bone formation, lipid metabolism, muscle cell proliferation, and growth. This suggests that LIF might be a rather trivial molecule, doing nothing special except for blastocyst implantation. Despite their limitations, this is perhaps what the knockout mice are also telling us.

The argument then comes down almost to a matter of faith. If LIF is trivial or redundant, why bother to have a LIF gene? Why busily produce LIF? Why produce membrane-displayed and soluble LIF receptors? Would the body engage in such purposeless pursuits? I think that this is so unlikely that my response would be to start looking more carefully, particularly at LIF^–/– mice.

If the verdict in favor of LIF as a valuable molecule is positive, if a little uncertain, what is the design advantage offered by LIF or its colleagues, such as IL-6, OSM, and IL-11? Is LIF any different from any other cytokine or hormone? Perhaps all of them are pleiotropic. Has it been that, to create a simplified order, we have assigned particular roles to individual agents, e.g., erythropoiesis for erythropoietin, platelet formation for thrombopoietin? The reality for classical hormones is quite different. An agent such as estrogen has effects on virtually every tissue in the body and it would not be too difficult to devise in vitro model systems where addition of insulin would produce remarkable and diverse responses. On the whole, endocrinologists have been remarkably silent about ascribing defined functions to their favorite molecules; they can be involved in many processes—granted, perhaps, often as bit players.

The notion of one regulator/one function may be a particular fantasy of hematologists. Even in hematology, there are no certain examples of such single-minded action even within hematopoietic populations, let alone with cells of other lineages.

The reality of regulator control in a mammalian organism may not be a series of Shakespearian declamations by major players but a continuous background of chatter as mainly redundant regulators interact with multiplicities of cell types, usually with no particular consequences other than to ensure continuing balanced interactions between the diverse populations. By selecting any one of these many interactions and examining it in isolation, we may ourselves be artificially building up a picture of an apparently important piece of biology, with the need somehow to integrate this with other very different, but also artificially created, phenomena.

So, is pleiotropy a man-made artifact originating from the mistaken notion that regulators should have single actions? Should LIF be allowed to sink quietly into obscurity as yet another "middle-aged" regulator, a retired enigma able to play many roles but only a few of which are of major importance? One thing is sure: LIF will not go away. It is needed by mouse ES cells and molecular biologists. Has it been a pathfinder? Yes, but what has it been trying to reveal: the unexpected superiority of a particular 4--helical molecule, or that our notions of the separateness of organ biology are incorrect and that regulators are needed that can interact with a surprising variety of cell types throughout the body?

	REFERENCES

Top Abstract Introduction LIF as a Candidate... LIF and Embryonic Stem... Consequences of Excess Levels... LIF Knockouts and Blastocyst... LIF Production Sites The Promiscuous LIF Receptor The Pleiotropic Actions of... Implications of the Pleiotropic... References

 

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