INVOLVEMENT OF C3A AND C5A IN INTERLEUKIN-8 SECRETION BY HUMAN POLYMORPHONUCLEAR CELLS IN RESPONSE TO CAPSULAR MATERIAL OF CRYPTOCOCCUS-NEOFORMANS

In a previous paper we demonstrated that human polymorphonuclear cells (PMN) in the presence of normal human serum (NHS) secrete proinflamma tory cytokines in response to Cryptococcus neoformans or its major cap sular component, glucuronoxylomannan (GXM). The hypothesis that activa tion of the complement system could be responsible for the observed ph enomenon is supported by the fact that encapsulated and acapsular C. n eoformans isolates are activators of the complement system and, in par ticular, large encapsulated isolates are powerful activators. In the p resent study we demonstrate that (i) interleukin-8 (IL-8) release in r esponse to acapsular or encapsulated strains of C. neoformans is signi ficantly reduced in the presence of heat-inactivated serum rather than NHS and is completely abrogated in the absence of human serum; (ii) G XM-induced IL-8 release is strictly dependent on the presence of NBS, is inhibited by specific antibodies to either C3a and C5 complement co mponents, and is completely abrogated by the combined ease of these an tibodies; (iii) the addition of purified C3a and C5a directly stimulat es IL-8 release by PMN; and (iv) monoclonal antibody to GXM in combina tion with GXM or encapsulated C. neoformans potentiates IL-8 release b y PMN. These data shed light on the mechanism involved in GXM-induced IL-8 secretion by PMN, provide an additional potential role for comple ment in the control of C. neoformans infections, and suggest a complex interplay between the complement system, humoral immunity, and cytoki ne regulation.