At the interface of environment-immune interactions: Cytokine and growth-factor receptors 1 S. R. Broussard* 2 , J. H. Zhou*, H. D. Venters*, R. M. Bluthe ´ **, G. G. Freund‡‡, R. W. Johnson‡, R. Dantzer**, and K. W. Kelley* *Laboratory of Immunophysiology and ‡Integrative Biology, Department of Animal Sciences and ‡‡College of Medicine, Department of Pathology, University of Illinois, Urbana, IL 61801 and **INRA-INSERM U394, Unite ´ de Recherches de Neurobiologie Integrative, 33077 Bordeaux, France ABSTRACT: Sickness in humans and animals re- sulting from infection with microbial pathogens leads to a perturbation in immune homeostasis and is charac- terized by fever, inactivity, and reduced appetite. This response to immune challenge is mediated by the induc- tion of proinflammatory cytokines, such as tumor necro- sis factor α (TNFα) and interleukin-1 (IL-1). These pro- inflammatory cytokines are the major reason that im- munologically 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 proinflamma- tory 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 resis- tance of hepatic GH receptors, leading to a significant reduction in plasma IGF-I. Resistance of the IGF-I re- ceptor at target tissues has been shown by TNFα inhib- iting the ability of IGF-I to promote protein synthesis in human myoblasts. The mechanism by which proin- Key Words: Cytokines, Growth Inhibitors, Growth Promoters, Insulin-like Growth Factor, Receptors, Tumor Necrosis Factor 2001 American Society of Animal Science. All rights reserved. J. Anim. Sci. 79(E. Suppl.):E268–E284 Introduction Pathological and economical sequelae of infectious, au- toimmune, and neoplastic diseases result from interac- tions among three critical components: the host, microbe, 1 *This research was supported by grants from the National Insti- tutes 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 Fish- eries. This paper was presented by K.W.K. at the ADSA/ASAS annual meeting that was held in Baltimore, Maryland, in a symposium enti- tled, “Nutritional and Environmental Factors Influencing the Im- mune System.” Received July 26, 2000. Accepted June 1, 2001. E268 flammatory 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 TNFα 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 TNFα impairs sensitiv- ity 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, insu- lin receptor substrate-2. This action of TNFα occurs at the very low concentration of 10 pg/mL. The TNF- induced receptor resistance decreases biological activ- ity 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 re- sistance). and environment (Webster, 1981). The classic experi- ment of Louis Pasteur in 1878 was the first to establish that cold stress reduces resistance of poultry to Bacillus anthracis (reviewed in Kelley, 1985). During the 1930s, Hans Selye recognized that acute stressors cause im- portant changes in tissues that are now known to form the immune system. These stress-induced changes in- clude an involution of the thymus gland, an increase in circulating granulocytes, and a reduction in blood lym- phocytes (reviewed in Selye, 1998). 2 Correspondence: 207 Edward R. Madigan Laboratory, 1201 West Gregory Drive (phone: (217) 333-5142; fax: (217) 244-5617; E-mail: broussar@uiuc.edu).