Daniel G. Remick

Cytokines are recognized as critical early mediators of organ injury. We attempted to determine whether or not severe hepatic ischemia/reperfusion injury results in tumor necrosis factor-alpha (TNF-alpha) release with subsequent local and systemic tissue injury. After 90 min of lobar hepatic ischemia, TNF was measurable during the reperfusion period in the plasma of all 14 experimental animals, with levels peaking between 9 and 352 pg/ml. Endotoxin was undetectable in the plasma of these animals. Pulmonary injury, as evidenced by a neutrophilic infiltrate, edema and intra-alveolar hemorrhage developed after hepatic reperfusion. The neutrophilic infiltrate was quantitated using a myeloperoxidase (MPO) assay; this demonstrated a significant increase in MPO after only 1 h of reperfusion. Anti-TNF antiserum pretreatment significantly reduced the pulmonary MPO after hepatic reperfusion. After a 12-h reperfusion period, there was histologic evidence of intra-alveolar hemorrhage and pulmonary edema. Morphometric assessment showed that pretreatment with anti-TNF antiserum was able to completely inhibit the development of pulmonary edema. Liver injury was quantitated by measuring serum glutamic pyruvic transaminase which showed peaks at 3 and 24 h. Anti-TNF antiserum pretreatment was able to significantly reduce both of these peak elevations. These data show that hepatic ischemia/reperfusion results in TNF production, and that this TNF is intimately associated with pulmonary and hepatic injury.

OBJECTIVE: This article reviews recent developments in cytokine biology that are relevant to clinical psychiatry. METHOD: The authors reviewed English-language literature of the last 15 years that pertains to the biology of cytokines with emphasis on central nervous system effects in general and psychiatric disorders in particular. RESULTS: Growing evidence suggests that, in addition to providing communication between immune cells, specific cytokines play a role in signaling the brain to produce neurochemical, neuroendocrine, neuroimmune, and behavioral changes. This signaling may be part of a generalized, comprehensive mechanism to mobilize resources in the face of physical and/or psychological stress and to maintain homeostasis. The clinical implications of these findings are far-reaching and include a possible role for cytokines in the pathophysiology of specific psychiatric disorders such as major depression, schizophrenia, and Alzheimer's disease. The effects of cytokines in the central nervous system may provide a possible mechanism for the "sickness behavior" of patients with severe infection or cancer, as well as for the neuropsychiatric adverse effects of treatment with interferons and interleukins. CONCLUSIONS: A better understanding of the role of cytokines in various brain activities will enhance knowledge of specific psychobiological mechanisms in health and disease and provide opportunities for novel treatment interventions.

Human endothelial cells produced a neutrophil chemotactic factor (NCF) upon stimulation with tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), or lipopolysaccharide (LPS). The expression of endothelial cell-derived NCF messenger RNA and biological activity was both time- and concentration-dependent. Maximal NCF mRNA expression occurred at 10 and at 2 nanograms per milliliter for TNF and IL-1 beta, respectively; mRNA expression was first observed 1 hour after stimulation and was maintained for at least 24 hours. In situ hybridization analysis showed that NCF mRNA peaked in treated cells by 24 hours, whereas unstimulated cells were negative. These studies demonstrated that endothelial cells may participate in neutrophil-mediated inflammation by synthesizing a chemotactic factor in response to specific monokines and LPS.

Tumor necrosis factor-alpha (TNF) is a macrophage-derived peptide that is known to be an important mediator in various physiologic and immunologic events. Although the effector function of TNF has received recent attention, there is relatively little information regarding factors that regulate TNF expression. Highly Ia-positive murine peritoneal macrophages obtained via complete Freund's adjuvant elicitation were challenged with lipopolysaccharide (LPS) and assessed for the production and regulation of TNF at the cellular and molecular levels. In response to 1 microgram/ml LPS, the kinetics of functionally active TNF reached a maximum at approximately 3-4 h. The plateau in TNF levels was concomitant with an accelerated increase in prostaglandin E2 production. The addition of exogenous PGE2 demonstrated a dose-dependent reduction in LPS-induced TNF activity at the cellular level, as well as a significant reduction in TNF mRNA accumulation as assessed by Northern blot and in situ hybridization analysis. The reduction in LPS-stimulated mRNA accumulation by PGE2 was shown to occur at least at the level of transcription, since nuclear run-off analysis showed a specific reduction in TNF transcripts. These studies demonstrate that PGE2 can regulate macrophage-derived TNF gene expression.