Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties.

We report the identification and purification of a new inflammatory monokine synthesized by the macrophage tumor cell line RAW 264.7 in response to endotoxin. This monokine, which we term "macrophage inflammatory protein" (MIP), is a doublet with an apparent molecular mass of approximately 8,000 daltons on SDS-PAGE but forms aggregates of greater than 2 x 10(6) daltons as assessed by gel filtration.

Restoration of the lipopolysaccharide-responsive phenotype in C3H/HeJ peritoneal macrophage-P388D1 cell hybrids.

The fusion of thioglycollate-elicited peritoneal macrophages from the lipopolysaccharide (LPS)-nonresponsive C3H/HeJ mouse strain to a hypoxanthine phosphoribosyltransferase (HPRT)-negative variant of the murine macrophage cell line P388D1 has resulted in the derivation of eight hybrid clones following HAT selection. Propidium-Iodide staining followed by flow cytometry has demonstrated that the DNA content of the hybrids represents the sum of the parents. Codominant expression of class I antigens from both parental haplotypes is observed in the hybrids.

Cachectin--Tumour necrosis factor: a cytokine that mediates injury initiated by invasive parasites.

The primary role for which the immune system evolved was a protective one, yet there is no doubt that immune mechanisms can also injure the host. Frequently cited examples of immune-mediated injury include complement-induced disease processes, diseases caused by immune complexes, or those that result from cell-mediated hypersensitivity. During the past few years however, it has become clear that the immune system can also express itself through the action of various cytokines.

Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog.

Cachectin/tumor necrosis factor has been implicated as a mediator of lethal endotoxemia, but the metabolic and hemodynamic responses to this macrophage-derived peptide have been incompletely characterized. Cachectin was administered by intra-arterial infusion in two groups of beagle dogs at lethal (100 micrograms per kilogram) and sublethal (10 micrograms per kilogram) doses. The infusion produced serum cachectin levels (1 to 50 nanomoles per liter) similar to those achieved after experimental endotoxemia.

Effect of gamma interferon on cachectin expression by mononuclear phagocytes. Reversal of the lpsd (endotoxin resistance) phenotype.

IFN-gamma permits the endotoxin-induced production of cachectin by C3H/HeJ (endotoxin resistant) macrophages, apparently by facilitating endotoxin-induced cachectin biosynthesis at both transcriptional and posttranscriptional levels. IFN-gamma cannot induce cachectin biosynthesis by itself, nor does it markedly enhance cachectin production by endotoxin-induced peritoneal macrophages obtained from endotoxin-responsive mice. Elucidation of the precise mechanism through which IFN-gamma influences cachectin biosynthesis may permit a better understanding of the molecular events that follow endotoxin-induced activation of macrophages.

Shock and tissue injury induced by recombinant human cachectin.

Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest.

Cachectin/tumor necrosis factor mediates changes of skeletal muscle plasma membrane potential.

Lethal infections are associated with cellular dysfunction as evidenced by a decrease in the resting transmembrane potential difference (Em) of skeletal muscle fibers. Endotoxin stimulation of macrophages evokes production of cachectin, a protein that has been implicated as a mediator of the lethal effects of endotoxemia. In the present study, rat skeletal muscle fiber Em decreased when incubated with recombinant human cachectin.

Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1.

Recombinant human tumor necrosis factor (rTNF alpha) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 microgram/kg) rTNF alpha and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 micrograms/kg) rTNF alpha produces biphasic fevers.

Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance.

Cachectin (tumor necrosis factor) is a macrophage hormone strongly implicated in the pathogenesis of endotoxin-induced shock. The availability of a DNA probe complementary to the cachectin messenger RNA (mRNA), as well as a specific antibody capable of recognizing the cachectin gene product, has made it possible to analyze the regulation of cachectin gene expression under a variety of conditions. Thioglycollate-elicited peritoneal macrophages obtained from mice contain a pool of cachectin mRNA that is not expressed as protein.

Cachectin and tumour necrosis factor as two sides of the same biological coin.

In response to invasive stimuli macrophages secrete cachectin, a multipotent protein. Prominent among its biological effects is the ability to induce wasting (cachexia) as well as a lethal state of shock. The identity of cachectin and tumour necrosis factor has led to a new view of its therapeutic potential.

Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators.

Recently, cDNA sequences have been reported for both human and murine tumor necrosis factor (TNF; cachectin). The coding region of the TNF genes is highly conserved between man and mouse; 80% homology is apparent at the amino acid level. We now observe that a 33-nucleotide sequence, comprised entirely of A and T residues and located in the 3'-untranslated region, is conserved in toto in the murine and human TNF mRNAs.

Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts.

Cachectin/TNF (tumor necrosis factor), an endotoxin-induced murine macrophage hormone implicated in the pathogenesis of cachexia and shock, has been found capable of stimulating collagenase and prostaglandin E2 (PGE2) production by isolated human synovial cells and dermal fibroblasts. This bioactivity associated with cachectin is comparable to that observed with the monokine interleukin 1 (IL-1), previously suggested as the major mediator of proteolysis. The ability of cachectin/TNF to stimulate collagenase and PGE2 production suggests that it may play a role in tissue destruction and remodelling, as these processes occur in inflammatory diseases.

Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo.

A highly specific radioreceptor assay for cachectin/tumor necrosis factor (TNF) was utilized to measure the time course of lipopolysaccharide (LPS)-induced hormone production in rabbits. Cachectin/TNF bioactivity was monitored in the same serum samples by measuring lipoprotein lipase (LPL) suppression in 3T3-L1 cells. Cachectin/TNF is produced in large quantities by LPS-treated rabbits without priming by bacillus Calmette Guérin, C.

Recombinant interleukin 1 suppresses lipoprotein lipase activity in 3T3-L1 cells.

Recombinant murine interleukin 1 (rIL 1) inhibits 3T3-L1 cell expression of lipoprotein lipase (LPL) activity when present in exceedingly dilute concentration (less than 10(-15) M). The extreme sensitivity of the adipocyte system to rIL 1 far exceeds that of the standard lymphocyte-activating factor assay. However, enzyme suppression is incomplete; even at micromolar concentrations, rIL 1 causes only about a 50% reduction in LPL activity.

Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin.

A highly specific polyclonal rabbit antiserum directed against murine cachectin/tumor necrosis factor (TNF) was prepared. When BALB/c mice were passively immunized with the antiserum or with purified immune globulin, they were protected against the lethal effect of the endotoxin lipopolysaccharide produced by Escherichia coli. The prophylactic effect was dose-dependent and was most effective when the antiserum was administered prior to the injection of the endotoxin.

A macrophage factor inhibits adipocyte gene expression: an in vitro model of cachexia.

Certain infections and malignancies in mammals cause the development of a condition known as cachexia in which the animal continues to lose weight, often while consuming an adequate diet. When macrophages are stimulated with an endotoxin, they produce a factor or factors, termed cachectin, that inhibits the activity of fat-producing (lipogenic) enzymes in cultured adipocytes. This effect may reflect one of the physiological bases for cachexia.