Interleukin-1-alpha (Dainippon Sumitomo Pharma/Roche)

T lymphocytes from subjects with active systemic lupus erythematosus (SLE) exhibit reduced cAMP-inducible, protein kinase A (PKA)-dependent phosphorylation of several intracellular substrates compared with healthy and disease controls. To ascertain whether the persistent T cell activation observed during active SLE can result in impaired PKA-dependent protein phosphorylation, normal T cells were activated in vitro by monoclonal anti-CD3-epsilon antibody and recombinant IL1-alpha (rIL1-alpha) for 24 hr. T cell activation, verified by IL2 mRNA, IL2 receptor-alpha (IL2R-alpha) mRNA, and IL2R-beta mRNA expression, did not diminish cAMP-inducible, PKA-dependent protein phosphorylation. We also tested the hypothesis that circulating factors present in active SLE serum can decrease cAMP-inducible total PKA phosphotransferase activity and PKA-dependent protein phosphorylation in normal T lymphocytes. T cells cultured for 24 hr in medium supplemented with 10% active SLE sera (from subjects who exhibited the defect of PKA-dependent protein phosphorylation) exhibited similar total PKA phosphotransferase activity and substrate phosphorylation as cells cultured in normal AB serum. Moreover, the addition of interferon-alpha (IFN-alpha) and/or immune complexes (IC) did not diminish either total PKA activity or PKA-dependent substrate phosphorylation. Lastly, we found that the defect of PKA-dependent protein phosphorylation in active SLE T cells could not be reversed by culturing the cells in culture medium supplemented with 10% AB serum for 24 hr. In conclusion, (a) deficient cAMP-inducible, PKA-dependent phosphorylation in SLE T cells is not reversible by culturing cells in vitro; (b) there is no evidence to support the concept that serum factors, including IC and IFN-alpha, can induce a defect of PKA-dependent protein phosphorylation in normal T cells.

Analysis of the role of interleukins in T cell ontogeny in vitro indicates that the regulation of T cell development involves interleukins (ILs) as well as thymic hormones (THs). In order to assess their respective roles in T lymphocyte development in vivo, chemically thymectomized mice were treated with ILs and THs. After 2 days of hydrocortisone treatment, aged mice showed acute thymic involution (weight was less than 30% of control) and reduced spleen size (less than 80% of control) with progressive recovery to 8 days. After 2 days of hydrocortisone treatment, adult mice were injected for 5 days with mixed buffy coat interleukins (BC-IL; 50 units IL2 equivalence), purified IL2 (50 units), rIL1 beta (4 ng), and thymosin fraction V (TF5; 100 micrograms). The animals were sacrificed and spleens and thymuses were analyzed for weight, cellularity, T cell number, subsets, and function as determined by proliferative responses to concanavalin A and ILs. BC-IL treatment increased the recovery of spleen and thymus weights and cellularity with corresponding augmentation of number and function of T lymphocytes; neither IL1 or IL2 or their combination had this effect. TF5 had no effect alone but strongly potentiated the effect of BC-IL on T lymphocyte function. These data indicate that BC-IL in combination with thymic peptides potently promotes T lymphocyte development. The combination may be therapeutically relevant for immunorestoration.