msh--4-nle-7-phe-alpha- and Dermatitis--Contact

Administration of the pituitary hormone alpha-melanocyte-stimulating hormone (alpha-MSH) to mice was found to inhibit a number of IL-1 and TNF-inducible biologic responses in situ. The ability of either IL-1 or TNF to cause fever, enhance plasma levels of acute phase proteins, and increase the numbers of peripheral blood neutrophils was inhibited by the simultaneous peripheral administration of this neuropeptide. In addition, alpha-MSH reversed the depressive influences of IL-1 or TNF on the effector phase of contact hypersensitivity (CH) responses in animals given an adoptive transfer of primed lymphocytes from hapten-sensitized donors. Intracerebral injection of nanogram quantities of alpha-MSH inhibited the ability of peripherally administered IL-1 or TNF to induce both fever and neutrophilia without affecting the increase in plasma levels of serum amyloid P and fibrinogen. Also, nanogram quantities of alpha-MSH given intracerebrally to normal mice did not reverse the depressed CH responses observed after peripheral IL-1 or TNF administration. These findings suggest that both fever and neutrophilia are linked to the direct action of IL-1 or TNF on the brain. This was supported by the observation that an intracerebral injection of IL-1 or TNF in low doses increased core body temperature and circulating neutrophil numbers without affecting plasma levels of acute phase proteins or CH responsiveness. Our results provide additional support for the hypothesis that bidirectional control exists between elements of the neuroendocrine and immune systems.

Topics: alpha-MSH; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Dermatitis, Contact; Female; Fever; Fibrinogen; Injections, Intravenous; Injections, Intraventricular; Interleukin-1; Leukocyte Count; Male; Mice; Mice, Inbred C3H; Neutrophils; Recombinant Proteins; Serum Amyloid A Protein; Tumor Necrosis Factor-alpha

The ability of i.v.-administered recombinant human interleukin 1 (IL 1 beta) to increase core body temperature, stimulate an increased production of serum amyloid P substance, and augment blood levels of circulating neutrophils in mice was inhibited in a dosage-dependent manner by administration of the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH). alpha-MSH administration was also capable of inhibiting the capacity of i.v.-administered IL 1 beta to enhance plasma levels of corticosterone and to depress the generation and/or elicitation of contact hypersensitivity responses to skin-reactive chemicals. An analog of alpha-MSH (Nle4, D-Phe7 alpha-MSH), known to be more potent than native alpha-MSH in a number of melanotropin-sensitive systems, was determined to be more active than alpha-MSH in the modification of these same in vivo responses. Neither alpha-MSH nor its analog were capable of altering the capacity of IL 1 to stimulate increased plasma levels in prostaglandin E2 (PGE2). In vitro, neither alpha-MSH nor its analog were capable of reducing the capacity of IL 1 to stimulate fibroblast production of PGE2 or to augment the proliferation of murine thymocytes exposed to phytohemagglutinin. The apparent selectivity associated with the regulatory influences of alpha-MSH on IL 1-induced responses in vivo suggests that this neuropeptide may function as an endogenous inhibitor of certain immunomodulatory and inflammatory activities of the cytokine IL 1.

Topics: alpha-MSH; Animals; Corticosterone; Dermatitis, Contact; Dinoprostone; Fever; Interleukin-1; Lymphocyte Activation; Melanocyte-Stimulating Hormones; Mice; Neutrophils; Prostaglandins E; Recombinant Proteins; Serum Amyloid P-Component