The protein portion of the immunosuppressive glycoprotein uromodulin is identical to the Tamm-Horsfall urinary glycoprotein and is synthesized in the kidney. Evidence that the glycoproteins are the same is based on amino acid sequence identity, immunologic cross-reactivity, and tissue localization to the thick ascending limb of Henle's loop. Nucleic acid sequencing of clones for uromodulin isolated from a complementary DNA bank from human kidney predicts a protein 639 amino acids in length, including a 24--amino acid leader sequence and a cysteine-rich mature protein with eight potential glycosylation sites. Uromodulin and preparations of Tamm-Horsfall glycoprotein bind to recombinant murine interleukin-1 (rIL-1) and human rIL-1 alpha, rIL-1 beta, and recombinant tumor necrosis factor (rTNF). Uromodulin isolated from urine of pregnant women by lectin adherence is more immunosuppressive than material isolated by the original salt-precipitation protocol of Tamm and Horsfall. Immunohistologic studies demonstrate that rIL-1 and rTNF bind to the same area of the human kidney that binds to antiserum specific for uromodulin. Thus, uromodulin (Tamm-Horsfall glycoprotein) may function as a unique renal regulatory glycoprotein that specifically binds to and regulates the circulating activity of a number of potent cytokines, including IL-1 and TNF.

Plasma insulin-like growth factor-I (IGF-I) concentrations are reported to decline with advancing age. Five IGF-binding proteins (IGF-BPs) have recently been characterized in human serum, although their biological role beyond circulatory transport of IGF-I is unknown. We studied plasma IGF-I (by RIA) and serum IGF-BPs (by Western ligand blotting) in healthy elderly (n = 21) and healthy young (n = 22) women to determine if aging alters IGF-I and its high affinity BPs. Plasma IGF-I was significantly lower in the elderly than in the young group (0.78 +/- 0.08 vs. 1.22 +/- 0.11 U/ml; P less than 0.005). The number and size of IGF-BPs did not differ between age groups, but the IGF-BP binding ratios (binding of one BP fraction/binding of all fractions) for the BP-53 acid-stable complex (41.5K and 38.5K BPs), the 30K IGF-BP, and the 24K IGF-BP were all lower in the elderly than in the young group (P less than 0.01 for each fraction, elderly vs. young). In contrast, the 34K IGF-BP binding ratio was significantly greater in the elderly than in the young (0.30 +/- 0.03 vs. 0.12 +/- 0.01; P less than 0.001) and correlated closely with advancing age (r = 0.64; P less than 0.01). The changes in IGF-BPs found in the elderly are quite similar to alterations in serum IGF-BPs previously reported in GH deficiency. Since several IGF-BPs in vitro have been shown to modulate the mitogenic activity of IGF-I, the serum IGF-BP changes noted above may be important for the growth and maintenance of connective tissue, muscle, and bone during the aging process.

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