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At the interface of environment-immune interactions: Cytokine and growth-factor receptors¹

S. R. Broussard^*,2, J. H. Zhou^*, H. D. Venters^*, R. M. Bluthé^**, G. G. Freund, R. W. Johnson, R. Dantzer^** and K. W. Kelley^*

^* Laboratory of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana, IL 61801 and Integrative Biology, Department of Animal Sciences, University of Illinois, Urbana, IL 61801 and College of Medicine, Department of Pathology, University of Illinois, Urbana, IL 61801 and ^** INRA-INSERM U394, Unité de Recherches de Neurobiologie Integrative, 33077 Bordeaux, France

² Correspondence: 207 Edward R. Madigan Laboratory, 1201 West Gregory Drive (phone: (217) 333-5142; fax: (217) 244-5617; E-mail: broussar{at}uiuc.edu).

Abstract

Sickness in humans and animals resulting from infection with microbial pathogens leads to a perturbation in immune homeostasis and is characterized by fever, inactivity, and reduced appetite. This response to immune challenge is mediated by the induction of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). These proinflammatory cytokines are the major reason that immunologically challenged animals fail to eat. Here we present another pathway by which proinflammatory cytokines reduce animal growth and productivity. We propose that activation of receptors for proinflammatory cytokines affects the somatotropic axis, as they do for the insulin receptor, by reducing sensitivity of GH receptors in the liver and that of IGF-I receptors in target tissue. Proinflammatory cytokines induce resistance of hepatic GH receptors, leading to a significant reduction in plasma IGF-I. Resistance of the IGF-I receptor at target tissues has been shown by TNF inhibiting the ability of IGF-I to promote protein synthesis in human myoblasts. The mechanism by which proinflammatory cytokines induce resistance of the IGF-I receptor occurs by cytokine and hormone receptor cross talk on a single cell. This hypothesis is supported by our recent findings that established TNF as a potent inhibitor of IGF-I receptor signaling in neurons, which leads to the silencing of survival signals (SOSS). The molecular mechanism by which TNF impairs sensitivity of the IGF-I receptor is not by directly killing the cell but by decreasing the capacity of IGF-I to tyrosine phosphorylate its downstream docking molecule, insulin receptor substrate-2. This action of TNF occurs at the very low concentration of 10 pg/mL. The TNFinduced receptor resistance decreases biological activity of IGF-I, resulting in decreased neuron survival. It is likely that the reduction in growth and productivity that occurs in diseased animals is also the result of cytokine and hormone receptor cross talk, resulting in a decrease in GH-induced hepatic IGF-I synthesis (GH receptor resistance) and a reduction in responsiveness of target tissues to IGF-I stimulation (IGF-I receptor resistance).

¹ *This research was supported by grants from the National Institutes of Health to K.W.K. (MH-12558) and R.W.J. (AG-16710) and to K.W.K. from the Pioneering Research Project in Biotechnology financed by the Japanese Ministry of Agriculture, Forestry and Fisheries. This paper was presented by K.W.K. at the ADSA/ASAS annual meeting that was held in Baltimore, Maryland, in a symposium entitled, "Nutritional and Environmental Factors Influencing the Immune System."

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