Human immunoglobulin preparation for intravenous use induces elevation of cellular cyclic adenosine 3':5'-monophosphate levels, resulting in suppression of tumour necrosis factor alpha and interleukin-1 production

We previously showed that human immunoglobulin preparation for intravenous use (IGIV) suppresses the in vitro production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) by rabbit peritoneal exudate cells (PEC) stimulated with lipopolysaccharide (LPS). In this study we investigated the mechanism of the suppression. IGIV treated at pH4 (pH4-G) was used as IGIV. Fc fragments of pH4-G, as well as untreated pH4-G, suppressed TNF-alpha and IL-1 production by rabbit PEC stimulated with LPS. The interaction of pH4-G with PEC also resulted in generation of cyclic adenosine 3':5'-monophosphate (cAMP), known to be an intracellular second messenger. N6, 2'-0-dibutyryl cAMP (BtcAMP), a lipid-soluble derivative of cAMP, and cholera toxin (CT), an adenylate cyclase activating agent, also suppressed the production of TNF-alpha and IL-1. Further N-[2-(methylamino) ethyl]-5-isoquinolinesulphonamide dihydrochloride (H-8), an inhibitor of cAMP-dependent protein kinases, abrogated the suppression by pH4-G of the productions. These results indicate that the binding of IGIV to PEC via Fc gamma receptors (Fc gamma R) induces the elevation of intracellular cAMP levels, resulting in the suppression of LPS-induced TNF-alpha and IL-1 productions.