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RWDD3 (RSUME), a small RWD-containing protein, has a central role in sumoylation by enhancing SUMO conjugation in the regulatory network of immune–inflammatory signals. RWDD3 increases Ikappabeta sumoylation and stability. In addition, RWDD3 inhibits TNF-alpha-induced kappaB-LUC (Luciferase) reporter activity, showing the functional consequence of Ikappabeta increased stability. RSUME-enhanced sumoylation of Ikappabeta leads to the inhibition of NF-kappabeta activity on two well-known inflammatory genes, IL-8 and cyclooxygenase-2 (Cox-2) and therefore may also favor anti-inflammatory pathways. Expression of RWDD3 was induced under hypoxic conditions and it has a potential role during vascularization. Both BMP-4 and RWDD3 may be interesting targets for inhibiting steps involved in pituitary tumorigenesis.