Alpha-melanocyte stimulating hormone regulation of tumor necrosis factor and interleukin 1-indicible biologic responses

The effect of alpha-Melanocyte-Stimulating Hormone (alpha-MSH) on the ability of Interleukin 1 (IL-1) and Tumor Necrosis Factor (TNF) to mediate biologic responses was investigated. Initial experiments show that mice injected with either semi-purified IL-1or human recombinant IL-1beta demonstrate the following responses: fever, increased hepatocyte production of serum amyloid P (SAP) and elevated peripheral blood neutrophils. However, these same IL-1-induced biological activities could be inhibited by the simultaneous administration of either native alpha-MSH or the more potent alpha-MSH analogue, Nle4, D-Phe7 alpha-MSH. In addition, both neuropeptides inhibited the ability of IL-1 to depress mice contact hypersensitivity (CH) response to skin reactive chemicals. In vitro, neither alpha-MSH nor its analogue depressed the capacity of IL-1 to stimulate fibroblast production of response to phytohemagglutinin. Treating mice with either human recombinant Il-1beta or Tumor Necrosis Factor alpha (TNF-alpha) induced similar in vivo bioactivities including: fever, increased hepatocyte production of SAP and fibrinogen, elevated peripheral blood neutrophils and depressed CH responses. Intravenous administration of alpha-MSH with either IL-1 or TNF was effective in inhibiting the biological processes of these cytokines. The ability of peripherally administered IL-1 or TNF to increase core body temperature and peripheral blood neutrophils numbers was inhibited by intra-cerebrally administered alpha-MSH. However, intra-cerebral (i.c.) injections of alpha-MSH failed to reverse the ability of either cytokine to stimulate liver production of acute phase proteins or to abrogate their depressive influence on CH responses. Central (i.c.) injections of either IL-1 or TNF resulted in fever and neutrophilia while CH responses and plasma acute phase protein levels remained normal. These results suggest that both fever and neutrophilia are regulated via the direct action of IL-1 or RNF on the brain while increased production of acute phase proteins and depressed CH responses result from the interaction of cytokines with specific peripheral organ systems. Furthermore, the data presented herein indicate that naturally occurring alpha-MSH may function as an endogenous antagonist of both IL-1 and TNF and therefore, can influence the physiological changes that occur during inflammatory processes and tumor necrosis.