Insights into the mechanism by which interferon-gamma improves macrophage function following hemorrhage and resuscitation

Abstract

Recent studies indicate that depressed macrophage (M phi) immune responses following hemorrhage can be restored by the administration of interferon (IFN)-gamma as an adjuvant to resuscitation. However, the mechanism of these effects remains unknown. An important component of the process of M phi activation in response to pathogens is the mobilization of intracellular calcium ([Ca2+]i). Since hemorrhage alters the M phi signal transduction system, the aim of this study, therefore, was to determine whether administration of IFN-gamma after hemorrhage restores this mode of macrophage signal transduction. To assess this, C3H/HeN mice were bled to and maintained at a mean blood pressure of 35 mm Hg for 1 hr and then adequately resuscitated. Mice then received either 40,000 units IFN-gamma/kg body wt or saline vehicle and were killed 2 hr posthemorrhage to obtain splenic M phi. These M phi were loaded with Fluo-3 AM (fluorescent [Ca+2]i probe) and their capacity to mobilize [Ca+2]i in response to stimulation with f-met-leu-phe (FMLP; bacterial peptide) was assessed on a laser cytometer. The results indicated that IFN-gamma restored the capacity of splenic M phi to mobilize [Ca+2]i in response to FMLP. Moreover, the results demonstrated that hemorrhage produced a marked increase in resting cAMP levels in these cells that were lowered to sham levels by the administration of IFN-gamma. Thus, it appears that IFN-gamma acts to restore M phi signal transductional capacity, thereby improving M phi-mediated immune functions following hemorrhage and resuscitation.