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Leukemia Inhibitory Factor, Interleukin 6, and Other Cytokines Using the GP130 Transducing Receptor: Roles in Inflammation and Injury

^a Novartis Pharma Research, Transplantation and Gene Therapy, Basel, Switzerland;
^b California Institute of Technology, Division of Biology, Pasadena, California, USA

Key Words. Neuroimmune • Arthritis • Acute phase • Autoimmune • Oncostatin M • Ciliary neurotrophic factor • Leukemia inhibitory factor • Interleukin 6

Dr. Paul H. Patterson, California Institute of Technology, Division of Biology, Pasadena, California 91125, USA.

	Abstract

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 
Inflammation refers to a complex set of mechanisms by which tissues respond to injury and infection. Among the many soluble mediators associated with this process, cytokines are known to be crucial in regulating a variety of cellular and molecular events. Leukemia inhibitory factor (LIF), interleukin 6 (IL-6), IL-11, and possibly other members of this cytokine family are key mediators in various inflammatory processes such as the acute-phase reaction, tissue damage, and infection. These cytokines can act in both pro-inflammatory and anti-inflammatory ways, depending on a number of variables. We emphasize here recent work utilizing knockout mice, which has highlighted the roles of LIF and IL-6, particularly in interactions between the immune and nervous systems.

	Introduction

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 
Inflammation is a general term used to describe the many diverse processes that tissues employ in response to infections by pathogens and injuries caused by toxic molecules or physical damage such as burns or cuts. Classically, the inflammatory reaction has been described by four cardinal signs: rubor (redness), tumor (swelling), dolor (pain), and calor (heat). These signs are characteristic for the initial phase of inflammation, termed the acute inflammatory response. This process can then develop into a chronic inflammatory condition. As shown schematically in Figure 1, within seconds after injury, the permeability of the surrounding capillaries is altered leading to increased blood flow and leaking of fluid into the surrounding tissue. In case of substantial tissue damage, this initial reaction is quickly followed by an infiltration of white blood cells, predominantly neutrophils, into the tissue. This cellular response can reach major proportions within a few hours of injury. In case of severe damage, this reaction is followed by the chronic inflammatory response. During the next few days, the affected tissue is infiltrated by mononuclear cells, primarily lymphocytes, macrophages, and mast cells. Substantial tissue remodeling can also occur during this phase. Over the next few weeks, the healing process continues and leads either to complete restoration of the normal tissue architecture or to scar formation. Very often, the inflammatory reaction is accompanied by additional events, such as fever, release of acute phase proteins from the liver, or a general activation of the immune system.

View larger version (16K): [in this window] [in a new window]   Figure 1. The inflammatory response.

	The Neuropoietic Cytokines

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 
The focus of this review is on the cytokine family currently comprised of leukemia inhibitory factor (LIF), interleukin 6 (IL-6), IL-11, ciliary neurotrophic factor (CNTF), oncostatin M (OSM), cardiotrophin-1 (CT-1) and growth-promoting activity. These proteins are grouped as a family, not because of sequence homology, but because of a shared four helical bundle structure [1-5], shared subunits in their receptor complexes, and in some cases, overlapping functions. One of the shared receptor subunits is the transmembrane signal transduction protein known as gp130 [6, 7]. The use of a common transducing subunit in the receptor complex explains the similarity, if not identity, in downstream events evoked by these cytokines. Signaling by all members of the family activates intracellular tyrosine kinases of the Janus family which then phosphorylate transcription factors of the STAT (signal transducers and activators of transcription) family. Alternatively, a second signaling pathway can be stimulated that involves mitogen-activated protein kinase (MAPK) and the activation of another set of transcription factors. Thus, at least two pathways can be regulated by these cytokines, and some of these kinases are involved in inflammation. Since considerable early work with these cytokines focused on the hematopoietic and nervous systems, we have referred to the family as the neuropoietic cytokines, for convenience. It is clear, however, that there are target cells for this family outside the neuropoietic systems.

	The Acute Phase Reaction

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 
Neuropoietic cytokines can trigger the expression of the acute phase reaction, causing the liver to quickly secrete into the circulation the acute phase proteins (APPs). The function of the APP is to control body homeostasis and to regulate the inflammatory reaction. Many neuropoietic cytokines stimulate the release of APP from cultured hepatocytes [8-12], while IL-6 appears to be a primary inducer of APP in vivo [13-15]. The acute phase reaction elicited by infection or tissue damage is drastically reduced in IL-6 knockout (KO) mice, while lipopolysaccharide (LPS)-triggered APP secretion is only slightly diminished in these mice [16-18]. In addition, systemic administration of neuropoietic cytokines can stimulate the production of APP. For example, CNTF injected intravenously into adult rats strongly increases the synthesis of haptoglobin [19], just as LIF injected into rhesus monkeys strongly increases APP levels in the serum [20]. In the context of the acute phase reaction, these neuropoietic cytokines therefore act as anti- inflammatory mediators [21].

	IL-6 in Acute and Chronic Inflammation

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 
Besides the systemic acute phase reaction, IL-6 is associated with several acute and chronic inflammatory diseases, including rheumatoid arthritis, acute pancreatitis, viral and bacterial meningitis, and Alzheimer's disease. Rheumatoid arthritis is a chronic inflammatory process affecting the joints [22, 23]. Elevated levels of IL-6 and the soluble IL-6 receptor have been found in the synovial fluids and serum of patients suffering from this disease [24-30], and IL-6 levels correlate with disease severity. While IL-6 KO mice apparently exhibit more pronounced proteoglycan depletion than wild types in zymosan-induced arthritis [31], IL-6 is required for the development of collagen-induced arthritis in mice [32]. Moreover, an anti-IL-6 receptor monoclonal antibody ameliorates symptoms in murine collagen-induced arthritis [33]. A preliminary clinical trial has reported positive results on treating refractory rheumatoid arthritis patients with a mouse anti-IL-6 monoclonal antibody [34]. Supporting this are recent confirmatory results with collagen-induced arthritis in monkeys and an open trial on refractory rheumatoid arthritis patients with a humanized anti-IL-6 receptor monoclonal antibody [35].

IL-6 levels are also correlated with symptom severity in acute pancreatitis [36]. Indeed, transgenic overexpression of IL-6 in the pancreas results in a severe inflammatory reaction associated with infiltration of mononuclear cells [37]. IL-6 is required for a normal response to tissue damage caused by turpentine or carrageenan injection [17, 38]. This cytokine is not required for activation of the hypothalamic-pituitary-adrenal (HPA) axis, however, as shown by a normal induction of corticosterone following LPS injection in IL-6 KO mice [17]. Despite this observation, however, expression of IL-6 in the central nervous system (CNS) is required for the fever response to peripheral injection of LPS or IL-1ß [39] ( Table 1). Moreover, systemic LPS delivery in IL-6 KO mice results in enhanced levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF)- and interferon- compared with those of wild-type mice [40].

IL-6 is detected in the CSF [50] and surrounding the amyloid deposits found in the brains of Alzheimer patients [51]. IL-6 levels also increase following peripheral nerve injury or axotomy of CNS neurons [52]. Moreover, the astrocyte and microglial reaction to axotomy and cryo-injury is reduced in IL-6 KO mice [53, 54]. In addition, there is a significant sexual dimorphism to the response to sciatic nerve section in that female IL-6 KO mice exhibit autonomy, a sign of neuropathic pain, much more strongly than male KOs or wild-type mice [38]. There are, however, a number of complex findings in the pain responses of the IL-6 KOs, and one interpretation is that this is due to the compensatory rise in other cytokines that is observed in the absence of IL-6 [55].

There has been a recent surge in our knowledge about the role of IL-6 in autoimmune diseases of the nervous system. T-helper lymphocytes from myasthenia gravis patients have more IL-6 receptors than controls [56]. There is a strong IL-6 response in the protracted, relapsing model of experimental autoimmune encephalomyelitis (PR-EAE) in DA rats. IL-6 mRNA-expressing cells are present in the CNS and lymph nodes in this model but not in acute EAE [57]. Administration of neutralizing antibodies to IL-6 can reduce EAE [58]. Moreover, four groups have shown that IL-6 KO mice are resistant to the induction of EAE [59-62]. These striking demonstrations of the role of IL-6 in initiating EAE support the idea of testing anti-IL-6 strategies in multiple sclerosis.

In each of these inflammatory conditions, IL-6 acts as a pro-inflammatory cytokine. As mentioned previously, however, IL-6 can downregulate the inflammatory reaction caused by various stimuli ( Table 2). This is the case during the acute phase reaction, where IL-6 suppresses the pro-inflammatory cytokines IL-1 and TNF [63]. In addition, IL-6 can protect against lung damage in a model of pulmonary inflammation [63]. It can also protect against septic shock [65], an activity shared by the neuropoietic cytokine IL-11 [66, 67].

	LIF in Acute and Chronic Inflammation

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

LIF has also been detected in the pleural effusions of patients suffering from infectious lung disease, e.g., tuberculosis [84], and in the bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome [85]. LIF is also present in the urine of patients undergoing acute rejection after kidney transplantation [86-89]. Local inflammatory processes, e.g., in the skin, have been shown to involve LIF as a mediator. Elevated levels of LIF transcripts are detected in the early phase of contact dermatitis [90]. Moreover, injection of LIF into the mouse ear causes an increase in ear thickness and a massive infiltration of leukocytes [91], and injection of LIF into the skin of the juvenile rat hindpaw elicits mechanical hypersensitivity [92]. On the other hand, the responses to intraplantar injection of complete Freund's adjuvant (CFA) (edema, IL-1 induction, and cellular infiltration) are significantly augmented in adult LIF KO mice compared to wild-type [93]. Moreover, local injection of LIF into the hindpaw diminishes the pain response and the induction of IL-1 and nerve growth factor caused by CFA [93]. Some of the variables that differ among these studies and that could explain the diverse results include the age of animals, concentration of LIF injected, and the use of CFA.

Levels of LIF mRNA are also strongly enhanced in various tissues during systemic inflammation triggered by LPS injection [94]. In addition, pretreatment of mice with neutralizing anti-LIF antibodies protects against a lethal dose of LPS [95]. These data indicate that LIF is one of the principal agents in the lethality associated with septic shock. Surprisingly, LIF injection prior to a challenge with a high dose of LPS protects against the lethal effects of endotoxin [96, 97], suggesting that LIF may also exert anti-inflammatory activities. Similarly, intratracheal coinjection of LIF and LPS inhibits the acute inflammatory response that is usually triggered by LPS alone [98]. Infiltration of neutrophils into the lung is affected, and LIF significantly reduces the amount of TNF secreted into the bronchoalveolar fluid. Treatment of a rabbit atherosclerosis model with LIF results in lower plasma cholesterol and fewer aortic fatty streaks and inhibits the development of cuff-induced carotid neointimal thickening without affecting monocyte invasion of the vessel wall [99].

In the kidney, induction of antiglomerular basement membrane nephritis rapidly upregulates LIF, and intraperitoneal delivery of LIF by mini-pump limits proteinuria, macrophage infiltration, and IL-1 and TNF- expression [100]. IL-6, in contrast, has complex effects on inflammation in the glomerulus [101]. Another difference among cytokine family members is that LIF and IL-6 transiently upregulate monocyte chemotactic protein (MCP)-1 in cultured glomerular mesangial cells, whereas OSM does not [102].

Unlike IL-6, LIF is required for the HPA stress response. LIF KO mice do not respond to immobilization stress with the normal rise in adrenocorticotrophic hormone (ACTH). Moreover, corticosterone levels do rise normally in response to LPS injection in the LIF KO mouse [103]. Consistent with these observations is the finding that LIF injection enhances ACTH and cortisone plasma levels, and LIF and LIF receptor are expressed in the mouse hypothalamus and pituitary and are upregulated by LPS injection [104].

	LIF in Neural Inflammation

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 
LIF plays a key role in the response of the CNS and peripheral nervous system (PNS) to injury and possibly infection. The mRNA for LIF is upregulated in the neurons and glia of human patients with subacute sclerosing panencephalitis, a long-term inflammatory measles virus infection [105]. A dramatic rise in LIF mRNA is also observed following sciatic or olfactory nerve transection, cortical stab wound, excitatory amino acid-induced injury to the spinal cord, and seizure [106-112]. In LIF KO mice, infiltration by neutrophils, macrophages, and mast cells is delayed compared with wild-type in both CNS and PNS lesions [113, 114]. These results are the opposite of those obtained for CFA injection in the skin of the LIF KO mouse and suggest that LIF could be chemotactic for inflammatory cells, at least in the nervous system. Indeed, LIF can induce chemotaxis in mouse peritoneal macrophages in a microchamber assay [113].

In addition to modulating the initial inflammatory response following neural injury, LIF also regulates the neuronal response to injury. Axotomy of sympathetic or sensory neurons in LIF KO mice does not cause the same upregulation of neuropeptides that occurs in wild-type [111, 115-117]. Since several of the neuropeptides normally induced by injury are known to be chemotactic for macrophages and can stimulate cytokine production by monocytes [118-121], LIF may regulate the inflammatory response by directly influencing immune cells, and/or indirectly via secondary mediators such as neuropeptides. In addition to regulating the gene expression of injured neurons, recent experiments with KO mice have also shown that LIF is required for the neuronal death and neurogenesis that follow axotomy of primary olfactory neurons [122]. It is also of interest for the neuromuscular junction that injured and diseased mouse skeletal muscle strongly upregulates LIF and IL-6 mRNA levels [123].

Like IL-6, LIF also modulates the astrocyte and microglial reaction to CNS lesion, with glial fibrillary acidic protein (GFAP) and microglial staining being reduced in the lesioned LIF KO cortex compared with lesioned wild-type [112]. LIF also regulates anti-GFAP staining in subpopulations of astrocytes in the normal adult brain, as shown by a difference between the LIF KO and wild-type [124]. This difference displays a striking sexual dimorphism, with the female null mutant displaying far less GFAP staining than the male. A deficit in GFAP staining was also reported in the neonatal CNS of the KO for the LIF receptor [125, 126]. The LIF receptor is also required for motor neuron development, but it is not yet clear if this corresponds to a dependence on LIF itself or another neuropoietic cytokine that utilizes the LIF receptor in its receptor complex [125]. Studies of double KO mice have shown that LIF and CNTF cooperate in the support of motor neurons in the normal adult mouse [127].

	Other Neuropoietic Cytokines in Inflammation

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 
Although there is less evidence to date, OSM may also regulate arthritis, along with IL-6 and LIF. Levels of OSM in rheumatoid arthritis synovial fluid correlate with leukocyte number [69, 128]. This cytokine also stimulates proteoglycan catabolism in pig cartilage explants as well as collagen catabolism in human and animal cartilage explants [129, 130]. In addition, several members of this cytokine family, including OSM, IL-6, IL-11, and CNTF inhibit proteoglycan synthesis in pig cartilage explants [130]. On the other hand, like LIF, OSM can inhibit bone resorption in culture assays [131]. Circulating levels of OSM are high in septic patients [132], and ectopic OSM expression in the pancreas results in signs of chronic inflammation [133]. Moreover, subcutaneous injection of OSM causes an acute inflammatory reaction, and OSM-immunoreactive cells resembling macrophages are observed infiltrating human aortic aneurysms, which is a chronic inflammatory condition [134]. Unfortunately, as there are no reports of an OSM KO mouse thus far, key experiments on the role of endogenous OSM remain for the future.

Another member of this cytokine family, IL-11, is also upregulated in synovial fluid from patients with rheumatoid or osteoarthritis [15, 69]. As mentioned above, IL-11 suppresses proteoglycan synthesis in articular cartilage [130]. In contrast, a preliminary account reports success using IL-11 to treat synovitis in HLA B27 transgenic rats, with a reduction in cartilage damage [135]. This cytokine also protects against hyperoxic lung injury in transgenic mice that overexpress IL-11 in that tissue [136]. Remarkably, IL-11 also exerts protective effects in the gastrointestinal tract in a variety of colitis models, in inflammatory bowel disease of HLA B-27 transgenic mice, and after chemotherapy and radiation [137-140]. These results are consistent with reports that IL-11 inhibits macrophage IL-1, TNF, and IL-12 production [66, 141, 142]. Pretreatment with IL-11 enhances survival in rodent models of toxic shock and sepsis, as well as a rabbit model of endotoxemia [67, 143, 144]. While several human clinical trials indicate that IL-11 will be a useful thrombopoietin [145], KO of the IL-11 (IL-11R) does not cause detectable deficits in hematopoiesis [146]. It will be important to examine such receptor KO mice as well as IL-11 KO mice for their inflammatory responses.

While the actions of family member CNTF have been carefully examined at the level of signal transduction, relatively few papers are available on its potential role in inflammation ( Tables 1 and 2). Along with other neuropoietic cytokines, circulating CNTF levels are elevated in septic shock patients [132]. This cytokine does inhibit TNF production following LPS injection in mice and can protect against death when coinjected with its soluble receptor [146]. This effect requires an intact HPA axis, as adrenalectomy abolishes the suppression of TNF and the protection against death. This cytokine can activate the HPA axis, causing elevation of serum corticosteroids, and it can act as a pyrogen [148-150].

While CNTF expression is increased in astrocytes during reactive gliosis, its mRNA is decreased following sciatic nerve transection [151-154]. Spinal cord transection in the adult rat results in rapid upregulation of CNTF receptor mRNA levels in motor neurons and CNTF mRNA in white matter [155]. In addition, entorhinal cortex lesion evokes upregulation of immunostaining for CNTF and its receptor in the astrocytes of the outer molecular layer of the dentate gyrus [156]. Cerebral spinal fluid from a number of CNS and PNS inflammatory diseases contain elevated levels of CNTF protein [157]. Injection of CNTF into the adult rat neocortex stimulates astrogliosis, and more microglia are observed [158], and similar results were obtained by transgenic overexpression of CNTF [154]. Curiously, there appear to be no reports on the course of inflammation in the nervous system of CNTF KO mice.

	Conclusions and Outlook

Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 
It is clear that the neuropoietic cytokines perform important functions in the regulation of inflammatory processes. These functions can be pro- or anti-inflammatory, and either function could be targeted for therapeutic purposes. In fact, preliminary results of trials manipulating IL-6 and IL-11 appear quite promising. A major issue for therapeutic use of these proteins is their pleiotropic effects. To circumvent this problem, these cytokines may be best applied or directed locally, as with viral vectors [159]. The pro-inflammatory properties of this family can be counteracted using dominant negative approaches, such as cytokines that bind receptors but confer no signal [160-163].

Another area of future work could involve the issue of why so many family members are utilized in an inflammatory condition (such as rheumatoid arthritis) when they all appear to exert the same biological effect (when tested on a common cell type that expresses the ligand binding subunit for each). Perhaps related is the question of how various family members can exert different effects on the same process, e.g., in arthritis models where IL-11 is anti-inflammatory and IL-6 is pro-inflammatory.

	Acknowledgments

 
The authors wish to thank the following for support of this research: National Institute for Neurological Disease and Stroke, McGrath Foundation, Spinal Cord Research Foundation, Della Martin Foundation, American Paralysis Association, Ralph L. Smith Foundation, Human Frontiers Science Program, and the Van Nuys Foundation (PHP); Novartis Pharma Research (RAG).

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Top Abstract Introduction The Neuropoietic Cytokines The Acute Phase Reaction IL-6 in Acute and... LIF in Acute and... LIF in Neural Inflammation Other Neuropoietic Cytokines in... Conclusions and Outlook References

 

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